rs28933068
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PS1PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000142.5(FGFR3):c.1620C>A(p.Asn540Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N540T) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 34)
Consequence
FGFR3
NM_000142.5 missense
NM_000142.5 missense
Scores
8
7
4
Clinical Significance
Conservation
PhyloP100: 3.02
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 22 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 domain Protein kinase (size 289) in uniprot entity FGFR3_HUMAN there are 14 pathogenic changes around while only 5 benign (74%) in NM_000142.5
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr4-1805643-A-C is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.99
PP5
Variant 4-1805644-C-A is Pathogenic according to our data. Variant chr4-1805644-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 16337.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-1805644-C-A is described in Lovd as [Pathogenic]. Variant chr4-1805644-C-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| FGFR3 | NM_000142.5 | c.1620C>A | p.Asn540Lys | missense_variant | 12/18 | ENST00000440486.8 | NP_000133.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| FGFR3 | ENST00000440486.8 | c.1620C>A | p.Asn540Lys | missense_variant | 12/18 | 5 | NM_000142.5 | ENSP00000414914 | P4 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
34
GnomAD4 exome Cov.: 34
GnomAD4 exome
Cov.:
34
GnomAD4 genome
GnomAD4 genome
Cov.:
34
Alfa
AF:
Hom.:
Bravo
AF:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:30Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:13
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 03, 2019 | The FGFR3 c.1620C>A; p.Asn540Lys variant (rs28933068; ClinVarID: 16337) is reported in the literature in multiple individuals affected with hypochondroplasia and achondroplasia (Bellus 1995, Deutz-Terlouw 1998, Xue 2014). Together with another variant resulting in the same amino acid change (c.1620C>G; p.Asn540Lys), these account for over 50% of all hypochondroplasia cases (Bellus 2000, Linnankivi 2012, Xue 2014). The asparagine at codon 540 is highly conserved, and functional analyses of the variant protein show significant reductions in protein expression and kinase activity (Krejci 2008, Raffioni 1998). Based on available information, this variant is considered to be pathogenic. References: Bellus GA et al. A recurrent mutation in the tyrosine kinase domain of fibroblast growth factor receptor 3 causes hypochondroplasia. Nat Genet. 1995 Jul;10(3):357-9. Bellus GA et al. Distinct missense mutations of the FGFR3 lys650 codon modulate receptor kinase activation and the severity of the skeletal dysplasia phenotype. Am J Hum Genet. 2000 Dec;67(6):1411-21. Deutz-Terlouw PP et al. Asn540Thr substitution in the fibroblast growth factor receptor 3 tyrosine kinase domain causing hypochondroplasia. Hum Mutat. 1998;Suppl 1:S62-5. 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. Linnankivi T et al. Neuroimaging and neurological findings in patients with hypochondroplasia and FGFR3 N540K mutation. Am J Med Genet A. 2012 Dec;158A(12):3119-25. Raffioni S et al. Effect of transmembrane and kinase domain mutations on fibroblast growth factor receptor 3 chimera signaling in PC12 cells. A model for the control of receptor tyrosine kinase activation. J Biol Chem. 1998 Dec 25;273(52):35250-9. Xue Y et al. FGFR3 mutation frequency in 324 cases from the International Skeletal Dysplasia Registry. Mol Genet Genomic Med. 2014 Nov;2(6):497-503. - |
| 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 | Revvity Omics, Revvity | Feb 01, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 10, 2022 | Published functional studies demonstrate this variant results in significantly reduced expression patterns and reduced STAT1 phosphorylation (Raffioni et al., 1998; Krejci et al., 2008); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22045636, 19088846, 23165795, 19449430, 23614116, 16575888, 9452043, 9857065, 25614871, 10360393, 24630288, 23573386, 24715719, 25505998, 16222682, 16020314, 8589686, 30335613, 30138938, 29620724, 30355600, 31130284, 33942288, 30755392, 32964447, 20301650, 34006472, 33726816, 7670477) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Aug 02, 2017 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 02, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Jan 22, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital | Dec 17, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Jan 10, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 22, 2024 | This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 540 of the FGFR3 protein (p.Asn540Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with sporadic or familial hypochondroplasia (PMID: 7670477, 8589686, 9452043, 11055896, 23165795, 25614871). It has also been observed to segregate with disease in related individuals. This variant is also known as c.1659C>A. ClinVar contains an entry for this variant (Variation ID: 16337). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt FGFR3 function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. - |
Hypochondroplasia Pathogenic:10Other:1
| 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 | Institute of Human Genetics, University of Leipzig Medical Center | Jan 22, 2024 | Criteria applied: PS4,PM5_STR,PS1,PS3_MOD,PM2_SUP,PP3,PM1_SUP - |
| 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 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Feb 23, 2023 | The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.69; 3Cnet: 0.72). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000016337). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 25614871). Different missense changes at the same codon (p.Asn540Asp, p.Asn540His, p.Asn540Ser, p.Asn540Thr) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000016344, VCV000016349, VCV000374828, VCV001325830). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
| not provided, no classification provided | literature only | GeneReviews | - | Most common pathogenic variant in hypochondroplasia - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Dec 03, 2021 | ACMG classification criteria: PS1 strong, PS3 supporting, PS4 strong, PM2 moderate - |
| Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | May 20, 2023 | The observed missense c.1620C>A(p.Asn540Lys) variant n FGFR3 gene has been reported previously in heterozygous state in multiple individuals affected with hypochondroplasia (Xue Y, et al., 2014; Linnankivi T, et al., 2012). This variant has also been reported to segregate with disease in related individuals. Functional studies of the variant protein show significant reductions in protein expression, reduced kinase activity, reduced STAT1 phosphorylation and support a damaging effect on the gene or gene product (Krejci P, et al., 2008; Bellus GA, et al., 2000). The p.Asn540Lys variant is absent in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic (multiple submissions). Multiple lines of computational evidence (Polyphen - Probably damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The amino acid change p.Asn540Lys in FGFR3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Asn at position 540 is changed to a Lys changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, no assertion criteria provided | research | Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital | May 31, 2019 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 11, 1999 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital | Jul 21, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Aug 29, 2023 | PS2, PS4, PM1, PM2, PM3, PP3 - |
Achondroplasia Pathogenic:5
| 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 | May 21, 2021 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS) | Apr 01, 2023 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital | Jul 21, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | DASA | Jan 05, 2022 | The c.1620C>A;p.(Asn540Lys) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 16337; PMID: 23573386; 7670477; 8589686; 25614871) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 11055896) - PS3_supporting.Same amino acid change as a previously established pathogenic variant regardless of nucleotide change(ClinVar: 16338; PMID 23165795; 25614871) - PS1. This variant is not present in population databases (rs28933068, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Pathogenic missense variant in this residue have been reported (Clinvar ID: 16349; 16344) - PM5. 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. - |
Neurodevelopmental delay Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille | - | - - |
FGFR3-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | May 22, 2024 | The FGFR3 c.1620C>A variant is predicted to result in the amino acid substitution p.Asn540Lys. This variant is reported to be the most common cause of hypochondroplasia (for example see: Bellus et al. 1995. PubMed ID: 7670477; Linnankivi et al. 2012. PubMed ID: 23165795; Mustafa et al. 2014. PubMed ID: 25505998; Xue et al. 2014. PubMed ID: 25614871; Maddirevula et al. 2018. PubMed ID: 29620724). This variant has been reported in the homozygous state in a patient with severe hypochondroplasia (De Rosa et al. 2014. PubMed ID: 24715719), and has also been reported in patients with thanatophoric dysplasia as part of a complex double de novo FGFR3 allele (Pannier et al. 2009. PubMed ID: 19449430; Marquis-Nicholson et al. 2013. PubMed ID: 23573386). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;.;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;.
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
N;.;.;.;.
MutationTaster
Benign
D;D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D
Polyphen
D;D;D;D;D
Vest4
MutPred
Gain of methylation at N540 (P = 0.007);.;.;.;.;
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