chr10-121520050-A-G
Variant summary
Our verdict is Pathogenic. Variant got 23 ACMG points: 23P and 0B. PS1PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_000141.5(FGFR2):c.868T>C(p.Trp290Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W290C) has been classified as Pathogenic.
Frequency
Consequence
NM_000141.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 23 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FGFR2 | NM_022970.4 | c.868T>C | p.Trp290Arg | missense_variant | 7/18 | ENST00000457416.7 | |
FGFR2 | NM_000141.5 | c.868T>C | p.Trp290Arg | missense_variant | 7/18 | ENST00000358487.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FGFR2 | ENST00000457416.7 | c.868T>C | p.Trp290Arg | missense_variant | 7/18 | 1 | NM_022970.4 | P4 | |
FGFR2 | ENST00000358487.10 | c.868T>C | p.Trp290Arg | missense_variant | 7/18 | 1 | NM_000141.5 | A2 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461886Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727244
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Crouzon syndrome Pathogenic:3
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 1995 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Department of Medical Genetics, Oslo University Hospital | Jun 03, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Sep 17, 2016 | - - |
not provided Pathogenic:3
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 | GeneDx | Oct 20, 2022 | Published functional studies demonstrate a disruption of signalling in both isoforms of the FGFR2 protein, and heterozygosity in a mouse model leads to craniosynostosis and an abnormal skull shape (Mai et al., 2010); 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: 31837199, 24928000, 7655462, 20503384, 12884424, 23431754, 27228464, 16418739, 24656465, 24127277, Pitirri2020[abstract]) - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
FGFR2-related craniosynostosis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 16, 2023 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects FGFR2 function (PMID: 20503384). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FGFR2 protein function. ClinVar contains an entry for this variant (Variation ID: 13283). This missense change has been observed in individuals with Crouzon syndrome (PMID: 7655462, 16418739, 23431754, 24127277, 24656465). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 290 of the FGFR2 protein (p.Trp290Arg). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at