FGF3
protein-codingfibroblast growth factor 3, the group of Receptor ligands|Fibroblast growth factor family
Gene summary
The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and cell survival activities and are involved in a variety of biological processes including embryonic development, cell growth, morphogenesis, tissue repair, tumor growth and invasion. This gene was identified by its similarity with mouse fgf3/int-2, a proto-oncogene activated in virally induced mammary tumors in the mouse. Frequent amplification of this gene has been found in human tumors, which may be important for neoplastic transformation and tumor progression. Studies of the similar genes in mouse and chicken suggested the role in inner ear formation. [provided by RefSeq, Jul 2008]
- INT2
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~9.4 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0012541
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0012541
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0012541
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0012541
Submitter: ClinGen
FGF3 was first reported in relation to autosomal recessive deafness with labyrinthine aplasia, microtia, and microdontiain (LAMM) syndrome in 2007 (Tekin et al., PMID 17236138). At least 11 variants (e.g. missense, nonsense, frameshift) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, experimental data. Variants in this gene have been reported in at least 12 probands in 6 publications (PMIDs 21480479, 21306635, 18435799, 17236138, 21306635, 18701883). Variants in this gene segregated with disease in at least 41 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence and experimental evidence (12 pts.) has been reached. The mechanism for disease appears to be homozygous loss of function based on the variants observed in patients. This gene-disease association is supported by animal models, expression studies and in vitro functional assays (PMIDs 8223243, 26995070, 29902227, 30504125). In summary, FGF3 is definitively associated with autosomal recessive deafness with LAMM 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 Hearing Loss Expert Panel on 5/21/2019 (SOP Version 6).
Inheritance Pattern: AR
Disease ID:MONDO:0012541
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Audiologic/Otolaryngologic; Craniofacial; Dental
Intervention: Audiologic/Otolaryngologic
Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development
Comments: The condition may typically be recognizable from physical examination
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to FGF3 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_005247.4. 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 | 29 | 30 | |||
| missense | 3 | 8 | 80 | 4 | 95 | |
| nonsense | 1 | 5 | 1 | 7 | ||
| start loss | 1 | 1 | ||||
| frameshift | 5 | 8 | 2 | 15 | ||
| splice donor/acceptor (+/-2bp) | 3 | 1 | 4 | |||
| Total | 10 | 24 | 85 | 33 | 0 | 152 |
Highest pathogenic variant AF is 0.000019216512
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_005238.1 | 3 | MANE Select | |
| Ensembl | ENSP00000334122.2 | 3 | MANE Select |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| fgf3 | Danio rerio | Structure: pharyngeal arch 3-7 Quality: morphology abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- PI3K-Akt signaling pathway - Homo sapiens (human)
- Gastric cancer - Homo sapiens (human)
- Melanoma - Homo sapiens (human)
- Breast cancer - Homo sapiens (human)
- Regulation of actin cytoskeleton - Homo sapiens (human)
Biological Process
- MAPK cascade
- signal transduction
- cell-cell signaling
- multicellular organism development
- positive regulation of cell population proliferation
Molecular Function
- protein tyrosine kinase activity
- Ras guanyl-nucleotide exchange factor activity
- fibroblast growth factor receptor binding
- protein binding
- growth factor activity
Cellular Component
- extracellular region
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000334134
- Coding exons
- 3
- Length
- 8801
- Individuals with no LoFs
- 125733
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 13
- Defined
- 125746
- p
- 0.0000517
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.118 | 140 | 136 | 1.03 | 0.0000101 | 1467 |
| Missense (PolyPhen) | 69 | 72.347 | 0.95373 | 686 | ||
| Synonymous | -0.00372 | 60 | 60.0 | 1.00 | 0.00000421 | 527 |
| Loss of Function | -0.0156 | 6 | 5.96 | 1.01 | 3.53e-7 | 71 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000079 | 0.000079 | rare |
| South Asian | 0.00010 | 0.000098 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Plays an important role in the regulation of embryonic development, cell proliferation, and cell differentiation. Required for normal ear development. {ECO:0000269|PubMed:8663044}.;
- Disease
- DISEASE: Deafness with labyrinthine aplasia, microtia and microdontia (LAMM) [MIM:610706]: Unique autosomal recessive syndrome characterized by type I microtia, microdontia, and profound congenital deafness associated with a complete absence of inner ear structures (Michel aplasia). {ECO:0000269|PubMed:17236138, ECO:0000269|PubMed:18435799}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.415
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.710
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |