rs387906678
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong
The NM_000141.5(FGFR2):c.1141T>G(p.Tyr381Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y381C) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000141.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 17 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FGFR2 | NM_022970.4 | c.1144T>G | p.Tyr382Asp | missense_variant | 9/18 | ENST00000457416.7 | |
FGFR2 | NM_000141.5 | c.1141T>G | p.Tyr381Asp | missense_variant | 9/18 | ENST00000358487.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FGFR2 | ENST00000457416.7 | c.1144T>G | p.Tyr382Asp | missense_variant | 9/18 | 1 | NM_022970.4 | P4 | |
FGFR2 | ENST00000358487.10 | c.1141T>G | p.Tyr381Asp | missense_variant | 9/18 | 1 | NM_000141.5 | A2 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 31
ClinVar
Submissions by phenotype
Bent bone dysplasia syndrome 1 Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 09, 2012 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Mar 31, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function (LoF) and gain of function (GoF) are known mechanisms of disease in this gene. Variants which are involved in LADD syndrome (MIM#149730) and bent bone dysplasia syndrome (MIM#614592), generally in the tyrosine kinase domain and hydrophobic transmembrane domain, respectively, exert a LoF effect. Variants involved in craniosynostosis (MIM#207410, 101200, 123790, 101600, 123500, 123150) are located within the extracellular ligand binding domain and exert a GoF effect (PMID: 27240702). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity in Crouzon syndrome (MIM#123500; GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from tyrosine to aspartic acid. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants in the transmembrane domain (DECIPHER, PMID: 27240702). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It is a recurrent variant in bent bone dysplasia syndrome (MIM#614592) and has been reported in at least ten individuals, with some confirmed de novo (PMID: 22387015, 26446305, 26573129, 27240702). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 20, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 26, 2021 | Not observed at significant frequency in large population cohorts (Lek et al., 2016); Published functional studies suggest a damaging effect, specifically, an increased accumulation in the nucleolus resulting in a disruption of nucleolar structure and increased ribosomal biogenesis that likely contributes to altered osteoblast differentiation (Neben, C, et al., 2017); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 24908667, 22387015, 25356970, 26573129, 26446305, 30620790, 29230096, 27240702, 28595297) - |
FGFR2-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 07, 2023 | The FGFR2 c.1141T>G variant is predicted to result in the amino acid substitution p.Tyr381Asp. This variant has been reported in the de novo or heterozygous states in individuals with bent bone dysplasia (Merrill et al. 2012. PubMed ID: 22387015; Stichelbout et al. 2015. PubMed ID: 26573129; Krakow et al. 2016. PubMed ID: 27240702). This variant has also been reported in the heterozygous state in an individual with craniosynostosis syndrome (Farwell et al. 2014. PubMed ID: 25356970. Table S3). Additionally, functional studies showed that this variant could reduce FGF canonical signaling and enhance nucleolar occupancy of FGFR2 at the ribosomal DNA promoter, therefore increasing osteoprogenitors cell proliferation and decreasing osteoblast differentiation (Merrill et al. 2012. PubMed ID: 22387015; Neben et al. 2014. PubMed ID: 24908667). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 29, 2012 | Please see table 3 in supplementary results of the main report. This variant has not been detected in conjunction with a pathogenic mutation to date. Allele frequency data in population-based cohorts is not currently available. This amino acid position is highly conserved in available vertebrate species.This alteration is predicted to be probably damaging with a score of 0.996 (sensitivity: 0.36; specificity: 0.97)This alteration is predicted to be tolerated with a score of 0.120 (conservation: 2.04) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at