rs28931614
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PS1PM1PM2PP3PP5_Very_Strong
The NM_000142.5(FGFR3):c.1138G>A(p.Gly380Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,460,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd.
Frequency
Genomes: not found (cov: 34)
Exomes 𝑓: 0.0000048 ( 0 hom. )
Consequence
FGFR3
NM_000142.5 missense
NM_000142.5 missense
Scores
7
8
4
Clinical Significance
Conservation
PhyloP100: 4.38
Genes affected
FGFR3 (HGNC:3690): (fibroblast growth factor receptor 3) 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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 17 ACMG points.
PS1
Transcript NM_000142.5 (FGFR3) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
PM1
In a transmembrane_region Helical (size 20) in uniprot entity FGFR3_HUMAN there are 7 pathogenic changes around while only 3 benign (70%) in NM_000142.5
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.836
PP5
Variant 4-1804392-G-A is Pathogenic according to our data. Variant chr4-1804392-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 16327.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-1804392-G-A is described in Lovd as [Pathogenic]. Variant chr4-1804392-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| FGFR3 | NM_000142.5 | c.1138G>A | p.Gly380Arg | missense_variant | 9/18 | ENST00000440486.8 | NP_000133.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| FGFR3 | ENST00000440486.8 | c.1138G>A | p.Gly380Arg | missense_variant | 9/18 | 5 | NM_000142.5 | ENSP00000414914 | P4 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
34
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1460854Hom.: 0 Cov.: 35 AF XY: 0.00000688 AC XY: 5AN XY: 726746
GnomAD4 exome
AF:
AC:
7
AN:
1460854
Hom.:
Cov.:
35
AF XY:
AC XY:
5
AN XY:
726746
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome
GnomAD4 genome
Cov.:
34
Alfa
AF:
Hom.:
Bravo
AF:
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:51Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Achondroplasia Pathogenic:27
| Pathogenic, criteria provided, single submitter | clinical testing | Center of Excellence in Genomics and Precision Dentistry, Faculty of Dentistry, Chulalongkorn University | - | The heterozygous missense variant, c.1138G>A (p.Gly380Arg), in FGFR3 was identified in a patient diagnosed with achondroplasia (ACH). This mutation was commonly identified in ACH patients (Bellus et al., 1995). - |
| Pathogenic, criteria provided, single submitter | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 14, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital | Dec 20, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | DASA | Feb 14, 2022 | Same amino acid variant as a previously established pathogenic variant regardless of nucleotide variant (Clinvar ID: 16328; PMID: 20301331) - PS1. Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 28230213) - PS3_moderate. The c.1138G>A;p.(Gly380Arg) missense variant has been observed in affected individual(s) (PMID: 32502767; 31994750; 20301331; 31299979; 28230213; 25691418) - PS4. This variant is not present in population databases (rs28931614, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 31994750) - PM6. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Nov 11, 2021 | The FGFR3 c.1138G>A (p.Gly380Arg) variant is a missense variant. Across a selection of literature, the p.Gly380Arg variant has been identified in a heterozygous state in at least 208 individuals (90%) with achondroplasia, occurring in a de novo state in the majority of cases (Bellus et al. 1995; Xue et al. 2014; Legare 2020). Additionally, the p.Gly380Arg variant has been observed in two individuals clinically diagnosed wth hypochondroplasia (Xue et al. 2014). The p.Gly380Arg variant is not reported in the Genome Aggregation Database (version 2.1.1 or version 3.2.1) in a region of good sequence coverage, suggesting that it is a rare variant. Both transgenic and knock-in mouse models that introduced the p.Gly380Arg variant into a human FGFR3 cDNA construct recapitulate the main phenotypic features of achondroplasia in a dose-dependent manner, including growth retardation, disproportionate shortening of the limbs, round head, mid-face hypoplasia at birth, and kyphosis progression during postnatal development (Segev et al. 2000; Lee et al. 2017). Based on the collective evidence, the p.Gly380Arg variant is classified as pathogenic for achondroplasia. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | May 27, 2021 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 15, 2011 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Centogene AG - the Rare Disease Company | Aug 19, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Jul 28, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City | Oct 11, 2020 | - - |
| Pathogenic, no assertion criteria provided | research | Department of Genetics, Beijing BioBiggen Technology Co., Ltd. | Jun 29, 2022 | - - |
| Pathogenic, criteria provided, single submitter | research | Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand | Jul 01, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Medical Genetics Center, Maternal and Child Health Hospital of Hubei Province | Jan 08, 2022 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare | Jun 18, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genesolutions, Medical Genetics Institutes, Ho Chi Minh City, Vietnam | Jun 22, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 27, 2021 | - - |
| Pathogenic, no assertion criteria provided | research | Institute Of Reproduction And Development, Obstetrics and Gynecology Hospital, Fudan University | Mar 16, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Breakthrough Genomics, Breakthrough Genomics | Sep 09, 2020 | This variant was previously reported in patients with achondroplasia, hypochondroplasia and with both achondroplasia and craniosynostosis [PMID: 22045636, 25614871, 21739570, 25691418]. Around 80% of individuals with achondroplasia have parents with average stature and have achondroplasia as the result of a de novo pathogenic variant and in more than 99% of cases of achondroplasia are caused by the identified variant (c.1138 G>A) and another point mutation (c.1138 G>C) resulting p.Gly380Arg substitution of the gene [PMID: 7913883, 20301331]. Functional studies indicate that the identified variant results in increased dimerization of the gene that subsequently increases its cellular activity in the absence of ligands [PMID: 23056398]. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India | Sep 05, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 24, 2023 | Variant summary: FGFR3 c.1138G>A (p.Gly380Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250348 control chromosomes. c.1138G>A has been reported in the literature in multiple individuals affected with Achondroplasia and observed to segregate with disease (Example: Falik-Zaccai_2000, Stoilov_1995 etc.). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function. One study shows that the mutation increases FGFR3 dimerization in a statistically significant way (Placone_2012) and another shows that mice recapitulate the phenotypes observed in ACH patients (dose dependent), including growth retardation, disproportionate shortening of the limbs, round head, mid-face hypoplasia at birth, and kyphosis progression during postnatal development (Lee_2017) . Twenty Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified as Pathogenic (n=28), VUS (n=1) . Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg | Aug 26, 2024 | This variant has been identified by standard clinical testing. Selected ACMG criteria: Pathogenic (II):PP5;PP4;PP3;PM2;PM1;PS3;PS1 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jun 24, 2022 | _x000D_ Criteria applied: PS1, PS3, PS4, PM1, PM2_SUP, PP3, PP4 - |
| Pathogenic, criteria provided, single submitter | curation | Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University | Dec 30, 2017 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | Jun 02, 2023 | The observed frameshift c.1574_1575del (p.Leu525ArgfsTer67) variant in ALDH5A1 gene has not been previously reported as pathogenic variant nor as a benign variant, to our knowledge. The p.Leu525ArgfsTer67 variant is absent in gnomAD Exomes. This variant has not been submitted to the ClinVar database. This variant causes a frameshift starting with codon Leucine 525, changes this amino acid to Arginine residue, and creates a premature Stop codon at position 67 of the new reading frame, denoted p.Leu525ArgfsTer67. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants in ALDH5A1 gene have been previously reported to be disease causing (Brennenstuhl et al., 2020). However, additional functional stuides will be required to prove the pathogenicity of this variant. For these reasons, this variant has been classified as Likely Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | New York Genome Center | Dec 07, 2022 | The de novo heterozygous c.1138G>A p.(Gly380Arg) missense variant is the most common pathogenic variant identified in individuals with achondroplasia [in approximately 98% of cases; PMID:20301331], and has been deposited to ClinVar database by multiple clinical laboratories as Pathogenic [Variation ID: 16327]. The c.1138G>A variant is located in exon 9 of this 18-exon gene and is predicted to replace glycine amino acid with arginine at position 380 of the encoded protein. In silico predictions are in favor of the variant’s deleterious effect [REVEL = 0.696]. In vitro functional studies indicated increased dimerization for the mutant protein resulting in ligand-independent phosphorylation of ERK and reduced proliferation of chondrocytes (PMID:23056398,19088846). A knock-in mouse model expressing the p.(Gly380Arg) variant recapitulated the phenotypes observed in human achondroplasia patients [PMID:28230213]. Based on the available evidence, the de novo heterozygous c.1138G>A p.(Gly380Arg) missense variant identified in FGFR3 gene is reported here as Pathogenic. - |
| Pathogenic, no assertion criteria provided | clinical testing | Department of Pediatrics, Taizhou Central Hospital, Taizhou University Hospital | Feb 01, 2024 | - - |
not provided Pathogenic:14
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 22, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 17, 2020 | More than 99% of cases of achondroplasia are caused by this variant (98% cases) and another point mutation (c.1138 G>C, 1% cases) resulting in arginine-for-glycine substitutions in amino acid 380 of the gene (Foldynova-Trantirkova et al., 2012); Published functional studies demonstrate an increase in dimerization of FGFR3 that subsequently increases its cellular activity in the absence of ligands (Placone et al., 2012; Webster et al., 1996); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 10360392, 10360393, 21739570, 25691418, 23740942, 23949953, 9857065, 28851938, 21324899, 11186940, 25614871, 11556601, 8599935, 27433940, 16841094, 19088846, 26136890, 8078586, 27370225, 29681095, 28679403, 28850094, 28230213, 28253570, 16475234, 28777845, 18266238, 30138938, 29620724, 30692697, 31218223, 31299979, 30712878, 32502767, 31994750, 32360156, 32668031, 33502061, 32712949, 33240318, 22045636, 23056398, 7913883) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 380 of the FGFR3 protein (p.Gly380Arg). This variant is not present in population databases (gnomAD no frequency). This is the most commonly observed variant in individuals with achondroplasia, accounting for ~70% of reported cases (PMID: 22045636, 25614871). It has also been reported in a few individuals with hypochondroplasia (PMID: 25614871) or with both achondroplasia and craniosynostosis (PMID: 21739570, 25691418). ClinVar contains an entry for this variant (Variation ID: 16327). A different variant (c.1138G>C) giving rise to the same protein effect observed here (p.Gly380Arg) has also been reported in individuals with achondroplasia. Together, these two variants (c.1138G>A and c.1138G>C) are observed in ~90% of individuals with achondroplasia (PMID: 22045636, 25614871). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Aug 15, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 04, 2023 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Jan 23, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 08, 2023 | The FGFR3 c.1138G>A; p.Gly380Arg variant (rs28931614) is the most common alteration identified in individuals with achondroplasia (Accogli 2015, Bessenyei 2013, Georgoulis 2011, Rousseau 1994, Xue 2014). Functional characterization of the variant protein in heterologous cells indicates increased dimerization at lower receptor concentrations (Placone 2012), resulting in ligand-independent phosphorylation of ERK and reduced proliferation of chondrocytes (Krejci 2008). A mouse model expressing the p.Gly380Arg variant recapitulates the skeletal alterations observed in human achondroplasia patients (Lee 2017). The variant is listed as pathogenic in ClinVar (Variation ID: 16327), and it is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Based on available information, the p.Gly380Arg variant is considered to be pathogenic. References: Accogli A et al. Association of achondroplasia with sagittal synostosis and scaphocephaly in two patients, an underestimated condition? Am J Med Genet A. 2015; 167A(3):646-52. PMID: 25691418. Bessenvei B et al. Achondroplasia with multiple-suture craniosynostosis: a report of a new case of this rare association. Am J Med Genet A. 2013; 161A(10):2641-4. PMID: 23949953. Georgoulis G et al. Achondroplasia with synostosis of multiple sutures. Am J Med Genet A. 2011; 155A(8):1969-71. PMID: 21739570. Huggins M et al. Achondroplasia-hypochondroplasia complex in a newborn infant. Am J Med Genet. 1999; 84(5):396-400.PMID: 10360392. Krejci P et al. Analysis of STAT1 activation by six FGFR3 mutants associated with skeletal dysplasia undermines dominant role of STAT1 in FGFR3 signaling in cartilage. PLoS One. 2008; 3(12):e3961. PMID: 19088846. Lee Y et al. Knock-in human FGFR3 achondroplasia mutation as a mouse model for human skeletal dysplasia. Sci Rep. 2017; 7:43220. PMID: 28230213. Placone J et al. Direct assessment of the effect of the Gly380Arg achondroplasia mutation on FGFR3 dimerization using quantitative imaging FRET. PLoS One. 2012; 7(10):e46678. PMID: 23056398. Rousseau F et al. Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia. Nature. 1994; 371(6494):252-4. PMID: 8078586. Xue Y et al. FGFR3 mutation frequency in 324 cases from the International Skeletal Dysplasia Registry. Mol Genet Genomic Med. 2014; 2(6):497-503. PMID: 25614871. - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Sep 08, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2023 | FGFR3: PS1, PS2, PM2, PS4:Moderate, PS3:Supporting - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | May 27, 2022 | - - |
Hypochondroplasia Pathogenic:2Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Jan 03, 2022 | Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000016327,VCV000016328, PMID:7913883,7913883, PS1_S). The variant has been observed in at least two similarly affected unrelated individuals (PMID: 25614871, PS4_M). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 23056398, PS3_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.696, 3CNET: 0.921, PP3_P). A missense variant is a common mechanism associated with Hypochondroplasia (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000000, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
| not provided, no classification provided | literature only | GeneReviews | - | Common pathogenic variant in achondroplasia - |
| Pathogenic, criteria provided, single submitter | clinical testing | Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India | May 09, 2022 | - - |
FGFR3-related disorder Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | - | This variant has been previously reported as a de novo or heterozygous change in patients primarily with achondroplasia (PMID: 8078586, 22045636, 25614871), while a few individuals have also been described with hypochondroplasia (PMID: 25614871) or with both achondroplasia and craniosynostosis (PMID: 21739570, 25691418).It is absent from the gnomAD population database and thus is presumed to be rare. The c.1144G>A (p.Gly382Arg) variant is predicted by multiple in silico tools to have a deleterious effect on protein function. This variant along with a different nucleotide change at the same location (c.1144G>C, (p.Gly382Arg)) are observed in approximately 90% of individuals with achondroplasia (PMID: 22045636, 25614871). Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.1144G>A (p.Gly382Arg) variant is classified as Pathogenic. - |
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 08, 2024 | The FGFR3 c.1138G>A variant is predicted to result in the amino acid substitution p.Gly380Arg. The p.Gly380Arg missense change is a recurrent pathogenic variant and is the most common causative variant in FGFR3 for autosomal dominant achondroplasia (Shiang et al. 1994. PubMed ID: 7913883; Bellus et al. 1995. PubMed ID: 7847369; Xue et al. 2014. PubMed ID: 25614871). This variant is interpreted as pathogenic. - |
not specified Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital | Jul 28, 2020 | - - |
Achondroplasia;C0005684:Malignant tumor of urinary bladder;C0153594:Malignant tumor of testis;C0265269:Levy-Hollister syndrome;C0334082:Epidermal nevus;C0410529:Hypochondroplasia;C0699790:Carcinoma of colon;C1300257:Thanatophoric dysplasia, type 2;C1864436:Muenke syndrome;C1864852:Camptodactyly-tall stature-scoliosis-hearing loss syndrome;C1868678:Thanatophoric dysplasia type 1;C2674173:Severe achondroplasia-developmental delay-acanthosis nigricans syndrome;C2677099:Crouzon syndrome-acanthosis nigricans syndrome;C4048328:Cervical cancer Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 29, 2022 | The c.1138G>A (p.G380R) alteration is located in exon 9 (coding exon 8) of the FGFR3 gene. This alteration results from a G to A substitution at nucleotide position 1138, causing the glycine (G) at amino acid position 380 to be replaced by an arginine (R). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration is the most common alteration to cause achondroplasia and has been reported in many unrelated individuals, including some de novo occurrences (Bellus, 1995; Xue, 2014; Zhang, 2021). Another alteration, c.1138G>C, resulting in the same protein change has been detected in individuals with achondroplasia (Xue, 2014). In HEK293 cells, this variant demonstrated a small, but statistically significant increase in FGFR3 dimerization (Placone, 2012). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. - |
Epidermal nevus Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 15, 2011 | - - |
Connective tissue disorder Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Jul 19, 2022 | - - |
Camptodactyly-tall stature-scoliosis-hearing loss syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | May 08, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;.;.
MutationTaster
Benign
D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N
REVEL
Pathogenic
Sift
Uncertain
D;T;D
Sift4G
Benign
T;T;T
Polyphen
P;D;D
Vest4
MutPred
Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);.;
MVP
MPC
1.0
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at