FGFR3
protein-codingfibroblast growth factor receptor 3, the group of I-set domain containing|CD molecules|Receptor tyrosine kinases
Gene summary
This gene encodes a member of the fibroblast growth factor receptor (FGFR) family, with its amino acid sequence being highly conserved between members and among divergent species. FGFR family members differ from one another in their ligand affinities and tissue distribution. A full-length representative protein would consist of an extracellular region, composed of three immunoglobulin-like domains, a single hydrophobic membrane-spanning segment and a cytoplasmic tyrosine kinase domain. The extracellular portion of the protein interacts with fibroblast growth factors, setting in motion a cascade of downstream signals, ultimately influencing mitogenesis and differentiation. This particular family member binds acidic and basic fibroblast growth hormone and plays a role in bone development and maintenance. Mutations in this gene lead to craniosynostosis and multiple types of skeletal dysplasia. [provided by RefSeq, Aug 2017]
- ACH
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~15.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0008546
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0859577
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0012504
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0018114
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0008547
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0012833
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0012833
Submitter: ClinGen
FGFR3 has been repeatedly described in association with autosomal dominant Crouzon Syndrome with Acanthosis Nigricans (CAN), a syndrome defined by the presence of the specific FGFR3 missense variant c.1172C>A (p.Ala391Glu). CAN is a rare, clinically heterogeneous disorder characterized by craniosynostosis during development, and thick, dark, velvety skin in body folds and creases, including the neck and underarms. FGFR3 was first reported in relation to CAN in 1995 (Meyers et al., PMID:7493034).The missense variant in FGFR3 has been reported in 22 probands in 13 publications (PMIDs: 7493034, 8880573, 10670894, 11426459, 17935505, 20199409, 27181494, 21136065, 29351036, 31016899, 32860240, 29620724, 27228464) included in this curation. The mechanism of pathogenicity is known to be GOF, the FGFR3 transmembrane dimer is stabilized -1.3 Kcal/mol by the creation of a new hydrogen bond, leading to increased ligand-independent activity and ligand-bound phosphorylation (PMID: 16384584). This gene-disease association is also supported by functional alteration experiments (PMIDs: 21536014, 23437153). In HEK293T cells, FGFR3/A391E was expressed in lower levels in the plasma membrane compared to WT. Additionally, cells with the A391E variant were shown to have enhanced ligand-independent activity compared to WT cells. FGFR3/A391E cells were also shown to have increased fgf1 ligand-dependent activity and increased Y647 and Y648 activity in the activation loop compared to WT. In summary, FGFR3 is definitively associated with autosomal dominant Crouzon Syndrom with Acanthosis Nigricans. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Craniofacial Malformations GCEP on the meeting date 11/18/2022 (SOP Version 8)
Inheritance Pattern: AD
Disease ID:MONDO:0008547
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0011274
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0012504
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0014658
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0011274
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0007872
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0007037
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0007037
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0012504
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0012504
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0007037
Submitter: ClinGen
*FGFR3* was first reported in relation to autosomal dominant achondroplasia in 1994 (Shiang et al., PMID: 7913883). AD Achondroplasia is characterized by short stature caused by rhizomelic shortening of the limbs, characteristic facies with frontal bossing and midface hypoplasia, exaggerated lumbar lordosis, limitation of elbow extension, genu varum, and trident hand. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in phenotypic variability. Therefore, the following disease entities have been split into multiple disease entities, SADDAN (OMIM:616482), Hypochondroplasia (OMIM:146000), Achondroplasia (OMIM: 100800), *FGFR3*-related Thanatophoric Dysplasia (Type I OMIM:187600 and Type II OMIM:187601), Crouzon Syndrome with acanthosis nigricans (OMIM:612247), Muenke Syndrome (OMIM:602849), and CATSHL Syndrome (OMIM:610474). The split curations for these gene disease relationships have been curated separately. Four missense variants that have been reported in 28 probands in 4 publications (PMIDs: 7758520, 7913883, 8078586, 16912704) are included in this curation meeting phenotypic criteria including short stature consistent with rhizomelic shortening of the limbs as well as characteristic facies with frontal bossing and midface hypoplasia, exaggerated lumbar lordosis, limitation of elbow extension, genu varum, and trident hand. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be GOF. This gene-disease relationship is also supported by biochemical function of the protein, functional alteration of variant(s), and a mouse model replicating disease in human patients (PMIDs: 9811582, 10200283, 14699054). In summary, there is definitive evidence supporting the relationship between *FGFR3* and autosomal dominant achondroplasia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Skeletal Disorders GCEP on the meeting date April, 4, 2022 (SOP Version 9).
Inheritance Pattern: AD
Disease ID:MONDO:0011274
Submitter: ClinGen
FGFR3 has been repeatedly described in association with autosomal dominant Muenke Syndrome, a syndrome defined by the presence of the specific FGFR3 missense variant c.749C>G (p.Pro250Arg). Muenke syndrome is characterized by considerable phenotypic variability even within a family and including phenotypic features such as coronal synostosis (bilateral and unilateral), synostosis of other sutures, macrocephaly, brachydactyly, hearing loss, and developmental delay. The missense variant in FGFR3 has been reported in at least 13 probands from 8 publications (PMIDs: 9042914,20592905,19449410, 24705944, 26740388,26740388,9600744). This gene-disease association is also supported by experimental evidence including animal models, and a ligand binding assay that characterized the ligand dependent gain of function to FGF9.(PMIDs: 19086028, 18818193, 22016144, 18818193). In summary, FGFR3 is definitively associated with autosomal dominant Muenke Syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Craniofacial Malformations Gene Curation Expert Panel on 12/16/2021.
Inheritance Pattern: AD
Disease ID:MONDO:0017042
Submitter: ClinGen
*FGFR3* was first reported in relation to AD thanatophoric dysplasia in 1995 (Tavormina et al., PMID: 7773297). Thanatophoric dysplasia is a severe skeletal disorder characterized by extremely short limbs and redundant skin on the arms and legs. Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found no difference in molecular mechanism, inheritance pattern, and phenotypic variability. Therefore, the following disease entities (thanatophoric dysplasia, type I, MIM:187600 and thanatophoric dysplasia, type II, MIM:187601) have been lumped into one disease entity, thanatophoric dysplasia. The split curations for SADDAN, CATSHL, hypochondroplasia, and achondroplasia have been curated separately. 3 missense, 3 stop-loss, and one indel variants that have been reported in 19 probands in 5 publications (PMIDs: 7773297, 7647778, 19752524, 29458880, 27028100) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of disease is reported to be gain of function. This gene-disease association is also supported by experimental evidence including mouse models and functional assays in a cell line and patient cells (PMIDs: 10861287, 9069288, 9438390). In summary, there is definitive evidence supporting the relationship between *FGFR3* and AD thanatophoric dysplasia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Skeletal Disorders GCEP on the meeting date January 13th, 2022 (SOP Version 8).
Inheritance Pattern: AD
Disease ID:MONDO:0011274
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0012833
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0100302
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0011274
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0007793
Submitter: ClinGen
*FGFR3* was first reported in relation to autosomal dominant hypochondroplasia in 1995 (Bellus et al., PMID: 7670477). Hypochondroplasia (HCH) is an autosomal dominant disorder characterized by short-limbed dwarfism, lumbar lordosis, short and broad bones, and caudad narrowing of the interpediculate distance of the lumbar spine. It shows some resemblance to achondroplasia, but is much milder and can be distinguished on clinical and radiographic grounds (Walker et al., PMID: 5564166). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in phenotypic variability. Therefore, the following disease entities have been split into multiple disease entities, SADDAN (OMIM:616482), Hypochondroplasia (OMIM:146000), Achondroplasia (OMIM: 100800), *FGFR3*-related Thanatophoric Dysplasia (Type I OMIM:187600 and Type II OMIM:187601), Crouzon Syndrome with acanthosis nigricans (OMIM:612247), Muenke Syndrome (OMIM:602849), and CATSHL Syndrome (OMIM:610474). The split curations for these gene disease relationships have been curated separately. Eleven variants (missense) that have been reported in fifteen probands in nine publications (PMIDs: 7670477, 8589686, 10777366, 11015576, 16912704, 27507911, 28181399, 29026271, 36859260) are included in this curation. The mechanism of pathogenicity is known to be gain of function. This gene-disease relationship is also supported by a mouse model recapitulating the mechanism of disease and phenocopying certain disease traits observed in human patients (PMIDs: 37345656). In summary, there is definitive evidence supporting the relationship between *FGFR3* and autosomal dominant hypochondroplasia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Skeletal Disorders GCEP on the meeting date October 4, 2021 (SOP Version 9).
Inheritance Pattern: AD
Disease ID:MONDO:0007793
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0008547
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0014658
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0008546
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0007793
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0007037
Submitter: PanelApp Australia
Inheritance Pattern: SD
Disease ID:MONDO:0012504
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0007037
Submitter: Orphanet
Inheritance Pattern: SD
Disease ID:MONDO:0012504
Submitter: ClinGen
*FGFR3* was first reported in relation to semidominant camptodactyly-tall stature-scoliosis-hearing loss (CATSHL) syndrome in 2006 (Toydemir et al., PMID: 17033969). CATSHL syndrome shows a continuum of disorder with more severe phenotypes in biallelic cases, and less severe phenotypes in monoallelic cases. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in phenotypic variability. Therefore, the following disease entities have been split into multiple disease entities, SADDAN (MIM:616482); Hypochondroplasia (MIM:146000); Achondroplasia (MIM: 100800); FGFR3-related Thanatophoric Dysplasia (Type I MIM:187600 and Type II MIM:187601); Crouzon Syndrome with acanthosis nigricans (MIM:612247); Muenke Syndrome (MIM:602849); and CATSHL Syndrome (MIM:610474). The split curations for these gene disease relationships have been curated separately. Four missense variants are associated with CATSHL syndrome and have been reported in five probands in five publications (PMIDs: 17033969, 27139183, 24864036, 37990933, 38307035). When inherited monoallelically, the missense variants might form heterodimers with wild type FGFR3 protein, inhibiting kinase activity needed for normal activation and binding to regulate bone growth, ultimately leading to a dominant negative loss-of-function mechanism of pathogenicity (Toydemir et al. 2006; PMID: 17033969). This gene-disease association is also supported by two mouse models and a zebrafish model (PMIDs: 8601314, 8630492, 32641982). This gene-disease pair was originally evaluated by the Skeletal Disorders GCEP on 3/2/2022 (SOP Version 8). It was reevaluated on 8/24/2026 (SOP Version 12). As a result of this reevaluation, new genetic evidence (PMIDs: 37990933, 38307035) was added, but the classification remained at moderate. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.
Inheritance Pattern: AD
Disease ID:MONDO:0008546
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0012833
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0007793
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0008547
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0007037
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0014658
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0011274
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0012504
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0008547
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0012833
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0007037
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0012833
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0008546
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0014658
Submitter: ClinGen
FGFR3 was first reported in relation to autosomal dominant severe achondroplasia-developmental delay-acanthosis nigricans (SADDAN) syndrome in in 1999 (Tavormina et al. 1999; PMID: 10053006). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in phenotypic variability. Therefore, the following disease entities have been split into multiple disease entities, SADDAN (OMIM:616482), Hypochondroplasia (OMIM:146000), Achondroplasia (OMIM: 100800), *FGFR3*-related Thanatophoric Dysplasia (Type I OMIM:187600 and Type II OMIM:187601), Crouzon Syndrome with acanthosis nigricans (OMIM:612247), Muenke Syndrome (OMIM:602849), and CATSHL Syndrome (OMIM:610474). The split curations for these gene disease relationships have been curated separately. Three missense variants in four probands from three publications (PMIDs: 10053006, 10377013, 25119967) are included in this curation. Additional probands reported to be diagnosed with SADDAN syndrome exist in the literature, but they were not scored in this curation due to difficulty in diagnosing developmental delay and acanthosis nigricans before a certain age. The mechanism of pathogenicity is GOF. A case report showing a GOF missense varaint K650M in cis with a LOF variant T651P leads to comparatively mild skeletal phenotype in the proband (PMID: 24352917). This gene-disease relationship is also supported by an animal model and in vitro functional assays (PMIDs: 11406607, 19088846, 29242050, 15292251, 16476447). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Skeletal Disorders Gene Curation Expert Panel on the meeting date 5/9/22 (SOP Version 8).
Inheritance Pattern: AD
Disease ID:MONDO:0007793
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0008546
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0007793
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0011274
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0012833
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Audiologic/Otolaryngologic; Craniofacial; Dermatologic; Musculoskeletal; Neurologic
Intervention: Audiologic/Otolaryngologic
Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development
Comments: Certain variants in FGFR3 (such as result in CATSHL or Muenke syndrome) can result in congenital hearing loss, and thecondition may not be recognized early
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to FGFR3 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000142.5. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 1 | 16 | 306 | 5 | 328 | |
| missense | 21 | 46 | 533 | 64 | 664 | |
| nonsense | 8 | 8 | ||||
| start loss | 2 | 2 | ||||
| frameshift | 1 | 2 | 17 | 20 | ||
| splice donor/acceptor (+/-2bp) | 10 | 10 | ||||
| Total | 22 | 49 | 586 | 370 | 5 | 1032 |
Highest pathogenic variant AF is 0.000016737335
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000133.1 | 17 | MANE Select | |
| Ensembl | ENSP00000414914.2 | 17 | MANE Select | |
| RefSeq | NP_001156685.1 | 17 | Standard | |
| RefSeq | NP_001341738.1 | 17 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| fgfr3 | Danio rerio | Structure: hematopoietic stem cell differentiation Quality: decreased occurrence abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- PI3K-Akt signaling pathway - Homo sapiens (human)
- Central carbon metabolism in cancer - Homo sapiens (human)
- Bladder cancer - Homo sapiens (human)
- Endocytosis - Homo sapiens (human)
- Regulation of actin cytoskeleton - Homo sapiens (human)
Biological Process
- MAPK cascade
- skeletal system development
- endochondral ossification
- chondrocyte differentiation
- endochondral bone growth
Molecular Function
- protein tyrosine kinase activity
- transmembrane receptor protein tyrosine kinase activity
- fibroblast growth factor-activated receptor activity
- Ras guanyl-nucleotide exchange factor activity
- protein binding
Cellular Component
- extracellular region
- nucleus
- endoplasmic reticulum
- Golgi apparatus
- plasma membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000340107
- Coding exons
- 17
- Length
- 15566
- Individuals with no LoFs
- 125514
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 36
- Defined
- 125550
- p
- 0.000143
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.26 | 458 | 540 | 0.848 | 0.0000388 | 5114 |
| Missense (PolyPhen) | 158 | 239.3 | 0.66025 | 2226 | ||
| Synonymous | -3.39 | 324 | 255 | 1.27 | 0.0000206 | 1680 |
| Loss of Function | 3.48 | 15 | 38.2 | 0.392 | 0.00000200 | 405 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000065 | 0.000062 | rare |
| Latino/Admixed American | 0.000096 | 0.000087 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00037 | 0.00033 | rare |
| Finnish | 0.000048 | 0.000046 | rare |
| European (Non-Finnish) | 0.00013 | 0.00012 | rare |
| South Asian | 0.00030 | 0.00029 | rare |
| Other | 0.00035 | 0.00033 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Tyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of cell proliferation, differentiation and apoptosis. Plays an essential role in the regulation of chondrocyte differentiation, proliferation and apoptosis, and is required for normal skeleton development. Regulates both osteogenesis and postnatal bone mineralization by osteoblasts. Promotes apoptosis in chondrocytes, but can also promote cancer cell proliferation. Required for normal development of the inner ear. Phosphorylates PLCG1, CBL and FRS2. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Plays a role in the regulation of vitamin D metabolism. Mutations that lead to constitutive kinase activation or impair normal FGFR3 maturation, internalization and degradation lead to aberrant signaling. Over-expressed or constitutively activated FGFR3 promotes activation of PTPN11/SHP2, STAT1, STAT5A and STAT5B. Secreted isoform 3 retains its capacity to bind FGF1 and FGF2 and hence may interfere with FGF signaling. {ECO:0000269|PubMed:10611230, ECO:0000269|PubMed:11294897, ECO:0000269|PubMed:11703096, ECO:0000269|PubMed:14534538, ECO:0000269|PubMed:16410555, ECO:0000269|PubMed:16597617, ECO:0000269|PubMed:17145761, ECO:0000269|PubMed:17311277, ECO:0000269|PubMed:17509076, ECO:0000269|PubMed:17561467, ECO:0000269|PubMed:19088846, ECO:0000269|PubMed:19286672, ECO:0000269|PubMed:8663044}.;
- Disease
- DISEASE: Achondroplasia (ACH) [MIM:100800]: A frequent form of short-limb dwarfism. It is characterized by a long, narrow trunk, short extremities, particularly in the proximal (rhizomelic) segments, a large head with frontal bossing, hypoplasia of the midface and a trident configuration of the hands. ACH is an autosomal dominant disease. {ECO:0000269|PubMed:10611230, ECO:0000269|PubMed:12297284, ECO:0000269|PubMed:7758520, ECO:0000269|PubMed:7847369, ECO:0000269|PubMed:8078586, ECO:0000269|PubMed:8599935}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Crouzon syndrome with acanthosis nigricans (CAN) [MIM:612247]: Classic Crouzon disease which is caused by mutations in the FGFR2 gene is characterized by craniosynostosis (premature fusion of the skull sutures), and facial hypoplasia. Crouzon syndrome with acanthosis nigricans (a skin disorder characterized by pigmentation anomalies), CAN, is considered to be an independent disorder from classic Crouzon syndrome. CAN is characterized by additional more severe physical manifestation, such as Chiari malformation, hydrocephalus, and atresia or stenosis of the choanas, and is caused by a specific mutation (Ala-391 to Glu) in the transmembrane domain of FGFR3. It is proposed to have an autosomal dominant mode of inheritance. {ECO:0000269|PubMed:17935505, ECO:0000269|PubMed:7493034}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Thanatophoric dysplasia 1 (TD1) [MIM:187600]: A neonatal lethal skeletal dysplasia. Affected individuals manifest severe shortening of the limbs with macrocephaly, narrow thorax, short ribs, and curved femurs. {ECO:0000269|PubMed:10360402, ECO:0000269|PubMed:10671061, ECO:0000269|PubMed:7773297, ECO:0000269|PubMed:8589699, ECO:0000269|PubMed:8845844, ECO:0000269|PubMed:9790257}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Thanatophoric dysplasia 2 (TD2) [MIM:187601]: A neonatal lethal skeletal dysplasia causing severe shortening of the limbs, narrow thorax and short ribs. Patients with thanatophoric dysplasia type 2 have straight femurs and cloverleaf skull. {ECO:0000269|PubMed:12297284, ECO:0000269|PubMed:7773297, ECO:0000269|PubMed:8754806}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Hypochondroplasia (HCH) [MIM:146000]: Autosomal dominant disease and is characterized by disproportionate short stature. It resembles achondroplasia, but with a less severe phenotype. {ECO:0000269|PubMed:10215410, ECO:0000269|PubMed:10777366, ECO:0000269|PubMed:11055896, ECO:0000269|PubMed:12707965, ECO:0000269|PubMed:7670477, ECO:0000269|PubMed:9452043}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Bladder cancer (BLC) [MIM:109800]: A malignancy originating in tissues of the urinary bladder. It often presents with multiple tumors appearing at different times and at different sites in the bladder. Most bladder cancers are transitional cell carcinomas that begin in cells that normally make up the inner lining of the bladder. Other types of bladder cancer include squamous cell carcinoma (cancer that begins in thin, flat cells) and adenocarcinoma (cancer that begins in cells that make and release mucus and other fluids). Bladder cancer is a complex disorder with both genetic and environmental influences. {ECO:0000269|PubMed:10471491, ECO:0000269|PubMed:11314002}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Somatic mutations can constitutively activate FGFR3.; DISEASE: Cervical cancer (CERCA) [MIM:603956]: A malignant neoplasm of the cervix, typically originating from a dysplastic or premalignant lesion previously present at the active squamocolumnar junction. The transformation from mild dysplastic to invasive carcinoma generally occurs slowly within several years, although the rate of this process varies widely. Carcinoma in situ is particularly known to precede invasive cervical cancer in most cases. Cervical cancer is strongly associated with infection by oncogenic types of human papillomavirus. {ECO:0000269|PubMed:10471491}. Note=The gene represented in this entry is involved in disease pathogenesis.; DISEASE: Camptodactyly, tall stature, and hearing loss syndrome (CATSHLS) [MIM:610474]: An autosomal dominant syndrome characterized by permanent and irreducible flexion of one or more fingers of the hand and/or feet, tall stature, scoliosis and/or a pectus excavatum, and hearing loss. Affected individuals have developmental delay and/or mental retardation, and several of these have microcephaly. Radiographic findings included tall vertebral bodies with irregular borders and broad femoral metaphyses with long tubular shafts. On audiological exam, each tested member have bilateral sensorineural hearing loss and absent otoacoustic emissions. The hearing loss was congenital or developed in early infancy, progressed variably in early childhood, and range from mild to severe. Computed tomography and magnetic resonance imaging reveal that the brain, middle ear, and inner ear are structurally normal. {ECO:0000269|PubMed:17033969}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Multiple myeloma (MM) [MIM:254500]: A malignant tumor of plasma cells usually arising in the bone marrow and characterized by diffuse involvement of the skeletal system, hyperglobulinemia, Bence-Jones proteinuria and anemia. Complications of multiple myeloma are bone pain, hypercalcemia, renal failure and spinal cord compression. The aberrant antibodies that are produced lead to impaired humoral immunity and patients have a high prevalence of infection. Amyloidosis may develop in some patients. Multiple myeloma is part of a spectrum of diseases ranging from monoclonal gammopathy of unknown significance (MGUS) to plasma cell leukemia. {ECO:0000269|PubMed:11529856, ECO:0000269|PubMed:9207791}. Note=The gene represented in this entry may be involved in disease pathogenesis. A chromosomal aberration involving FGFR3 is found in multiple myeloma. Translocation t(4;14)(p16.3;q32.3) with the IgH locus.; DISEASE: Lacrimo-auriculo-dento-digital syndrome (LADDS) [MIM:149730]: An autosomal dominant ectodermal dysplasia, a heterogeneous group of disorders due to abnormal development of two or more ectodermal structures. Lacrimo-auriculo-dento-digital syndrome is characterized by aplastic/hypoplastic lacrimal and salivary glands and ducts, cup-shaped ears, hearing loss, hypodontia and enamel hypoplasia, and distal limb segments anomalies. In addition to these cardinal features, facial dysmorphism, malformations of the kidney and respiratory system and abnormal genitalia have been reported. Craniosynostosis and severe syndactyly are not observed. {ECO:0000269|PubMed:16501574}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Keratinocytic non-epidermolytic nevus (KNEN) [MIM:162900]: Epidermal nevi of the common, non-organoid and non- epidermolytic type are benign skin lesions and may vary in their extent from a single (usually linear) lesion to widespread and systematized involvement. They may be present at birth or develop early during childhood. {ECO:0000269|PubMed:16841094}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Muenke syndrome (MNKS) [MIM:602849]: A condition characterized by premature closure of coronal suture of skull during development (coronal craniosynostosis), which affects the shape of the head and face. It may be uni- or bilateral. When bilateral, it is characterized by a skull with a small antero- posterior diameter (brachycephaly), often with a decrease in the depth of the orbits and hypoplasia of the maxillae. Unilateral closure of the coronal sutures leads to flattening of the orbit on the involved side (plagiocephaly). The intellect is normal. In addition to coronal craniosynostosis some affected individuals show skeletal abnormalities of hands and feet, sensorineural hearing loss, mental retardation and respiratory insufficiency. {ECO:0000269|PubMed:11746040, ECO:0000269|PubMed:9042914, ECO:0000269|PubMed:9950359}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Keratosis, seborrheic (KERSEB) [MIM:182000]: A common benign skin tumor. Seborrheic keratoses usually begin with the appearance of one or more sharply defined, light brown, flat macules. The lesions may be sparse or numerous. As they initially grow, they develop a velvety to finely verrucous surface, followed by an uneven warty surface with multiple plugged follicles and a dull or lackluster appearance. {ECO:0000269|PubMed:15772091}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Testicular germ cell tumor (TGCT) [MIM:273300]: A common malignancy in males representing 95% of all testicular neoplasms. TGCTs have various pathologic subtypes including: unclassified intratubular germ cell neoplasia, seminoma (including cases with syncytiotrophoblastic cells), spermatocytic seminoma, embryonal carcinoma, yolk sac tumor, choriocarcinoma, and teratoma. {ECO:0000269|PubMed:19855393}. Note=The gene represented in this entry may be involved in disease pathogenesis.; DISEASE: Achondroplasia, severe, with developmental delay and acanthosis nigricans (SADDAN) [MIM:616482]: A severe form of achondroplasia associated with developmental delay and acanthosis nigricans. Patients manifest short-limb dwarfism, with a long, narrow trunk, short extremities, particularly in the proximal (rhizomelic) segments, a large head with frontal bossing, hypoplasia of the midface and a trident configuration of the hands. Acanthosis nigricans is a skin condition characterized by brown-pigmented, velvety verrucosities in body folds and creases. {ECO:0000269|PubMed:10053006}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.785
Intolerance Scores
- LoFtool
- 0.0225
- RVIS EVS
- -2.05
- RVIS percentile EVS
- 1.64
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.837
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |