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rs28933068

Variant summary

Our verdict is Pathogenic. Variant got 25 ACMG points: 25P and 0B. PS1_Very_StrongPM1PM2_SupportingPM5PP3_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 Genomes 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 Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N540D) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 34)

Consequence

FGFR3
NM_000142.5 missense

Scores

8
7
4

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:26O:1

Conservation

PhyloP100: 3.02

Links

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 25 ACMG points.

PS1
?
Transcript NM_000142.5 (FGFR3) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 16338
PM1
?
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000142.5
PM2
?
Very rare variant; Number of alleles below threshold, Median coverage is 34.
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr4-1805643-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 16344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
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 UniProt
FGFR3NM_000142.5 linkuse as main transcriptc.1620C>A p.Asn540Lys missense_variant 12/18 ENST00000440486.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
FGFR3ENST00000440486.8 linkuse as main transcriptc.1620C>A p.Asn540Lys missense_variant 12/185 NM_000142.5 P4P22607-1

Frequencies

GnomAD3 genomes
Cov.:
34
Alfa
AF:
0.0000237
Hom.:
0
Bravo
AF:
0.00000756

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:26Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:12
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 03, 2019The 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, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenApr 01, 2018- -
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jun 02, 2018- -
Pathogenic, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
Pathogenic, criteria provided, single submitterclinical testingBlueprint GeneticsJan 22, 2020- -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, Revvity OmicsFeb 01, 2022- -
Pathogenic, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Pathogenic, criteria provided, single submitterclinical testingAl Jalila Children's Genomics Center, Al Jalila Childrens Speciality HospitalDec 17, 2022- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxMar 10, 2022Published 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 submitterclinical testingClinical Genetics and Genomics, Karolinska University HospitalAug 02, 2017- -
Pathogenic, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Pathogenic, criteria provided, single submitterclinical testingInvitaeNov 01, 2022This 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. For these reasons, this variant has been classified as Pathogenic. -
Hypochondroplasia Pathogenic:8Other:1
Pathogenic, no assertion criteria providedclinical testingClinical Molecular Genetics Laboratory, Johns Hopkins All Children's HospitalJul 21, 2015- -
Pathogenic, no assertion criteria providedliterature onlyOMIMJun 11, 1999- -
Pathogenic, criteria provided, single submitterclinical testingGreenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic CenterAug 29, 2023PS2, PS4, PM1, PM2, PM3, PP3 -
Pathogenic, criteria provided, single submitterclinical testingLaboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert EinsteinDec 03, 2021ACMG classification criteria: PS1 strong, PS3 supporting, PS4 strong, PM2 moderate -
Pathogenic, criteria provided, single submitterclinical testing3billionFeb 23, 2023The 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. -
Pathogenic, no assertion criteria providedresearchBeijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College HospitalMay 31, 2019- -
not provided, no classification providedliterature onlyGeneReviews-Most common pathogenic variant in hypochondroplasia -
Pathogenic, criteria provided, single submitterclinical testingKasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, IndiaMay 09, 2022- -
Pathogenic, no assertion criteria providedclinical testingBioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic HealthcareJun 18, 2018- -
Achondroplasia Pathogenic:5
Pathogenic, criteria provided, single submitterclinical testingMedical Genetics Center, Maternal and Child Health Hospital of Hubei ProvinceMay 21, 2021- -
Pathogenic, no assertion criteria providedclinical testingClinical Molecular Genetics Laboratory, Johns Hopkins All Children's HospitalJul 21, 2015- -
Pathogenic, criteria provided, single submitterresearchDivision of Human Genetics, National Health Laboratory Service/University of the WitwatersrandJul 01, 2023- -
Pathogenic, criteria provided, single submitterclinical testingDASAJan 05, 2022The 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. -
Pathogenic, no assertion criteria providedclinical testingClinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)Apr 01, 2023- -
Neurodevelopmental delay Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingCentre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Uncertain
0.12
D
BayesDel_noAF
Uncertain
-0.060
Cadd
Uncertain
24
Dann
Uncertain
0.99
DEOGEN2
Pathogenic
0.89
D;D;.;.;.
Eigen
Benign
0.15
Eigen_PC
Benign
0.16
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.94
D;D;D;D;.
M_CAP
Pathogenic
0.91
D
MetaRNN
Pathogenic
0.99
D;D;D;D;D
MetaSVM
Uncertain
0.18
D
MutationAssessor
Benign
-0.10
N;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D
PrimateAI
Pathogenic
0.85
D
PROVEAN
Pathogenic
-5.3
D;D;D;D;D
REVEL
Pathogenic
0.69
Sift
Pathogenic
0.0
D;D;D;D;D
Sift4G
Uncertain
0.0020
D;D;D;D;D
Polyphen
1.0
D;D;D;D;D
Vest4
1.0
MutPred
0.90
Gain of methylation at N540 (P = 0.007);.;.;.;.;
MVP
0.95
MPC
1.0
ClinPred
1.0
D
GERP RS
3.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.97
gMVP
0.81

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs28933068; hg19: chr4-1807371; API