rs1057519036
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong
The NM_000141.5(FGFR2):c.826T>G(p.Phe276Val) 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. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 33)
Consequence
FGFR2
NM_000141.5 missense
NM_000141.5 missense
Scores
12
3
2
Clinical Significance
Conservation
PhyloP100: 9.32
Genes affected
FGFR2 (HGNC:3689): (fibroblast growth factor receptor 2) The protein encoded by this gene is a member of the fibroblast growth factor receptor family, where amino acid sequence is highly conserved between members and throughout evolution. FGFR family members differ from one another in their ligand affinities and tissue distribution. A full-length representative protein consists 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 is a high-affinity receptor for acidic, basic and/or keratinocyte growth factor, depending on the isoform. Mutations in this gene are associated with Crouzon syndrome, Pfeiffer syndrome, Craniosynostosis, Apert syndrome, Jackson-Weiss syndrome, Beare-Stevenson cutis gyrata syndrome, Saethre-Chotzen syndrome, and syndromic craniosynostosis. Multiple alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Jan 2009]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 17 ACMG points.
PM1
?
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000141.5
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, FGFR2
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.968
PP5
?
Variant 10-121520092-A-C is Pathogenic according to our data. Variant chr10-121520092-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 374809.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-121520092-A-C is described in Lovd as [Pathogenic]. Variant chr10-121520092-A-C is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FGFR2 | NM_022970.4 | c.826T>G | p.Phe276Val | missense_variant | 7/18 | ENST00000457416.7 | |
FGFR2 | NM_000141.5 | c.826T>G | p.Phe276Val | missense_variant | 7/18 | ENST00000358487.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FGFR2 | ENST00000457416.7 | c.826T>G | p.Phe276Val | missense_variant | 7/18 | 1 | NM_022970.4 | P4 | |
FGFR2 | ENST00000358487.10 | c.826T>G | p.Phe276Val | missense_variant | 7/18 | 1 | NM_000141.5 | A2 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 01, 2022 | Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 24656465, 23754559, 24127277, 9521581, 22355256, 11173845, 11781872, 10633130, 10394936, 17693524, 10541159, 25271085, 35372644, 32178948) - |
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 | 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 | Nov 27, 2023 | This sequence change replaces phenylalanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 276 of the FGFR2 protein (p.Phe276Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with craniosynostosis conditions, including Crouzon syndrome and Pfeiffer syndrome (PMID: 9521581, 10394936, 10633130, 11781872, 24127277, 24656465). ClinVar contains an entry for this variant (Variation ID: 374809). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. - |
Crouzon syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Sep 17, 2016 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;.;D;.;D;D;D;D;D;D;D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;.;D;.;D;T;D;D;D;D;D;D;D;D
Sift4G
Benign
T;T;D;T;T;D;T;D;D;D;D;D;D;.
Polyphen
D;.;.;.;P;.;.;.;.;.;P;P;.;.
Vest4
MutPred
0.84
.;.;Loss of catalytic residue at F276 (P = 0.0054);.;.;Loss of catalytic residue at F276 (P = 0.0054);.;Loss of catalytic residue at F276 (P = 0.0054);Loss of catalytic residue at F276 (P = 0.0054);Loss of catalytic residue at F276 (P = 0.0054);.;Loss of catalytic residue at F276 (P = 0.0054);Loss of catalytic residue at F276 (P = 0.0054);.;
MVP
MPC
1.3
ClinPred
D
GERP RS
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