rs1358919643
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1PM2PP2PP5BP4
The NM_000141.5(FGFR2):c.940G>T(p.Ala314Ser) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A314A) has been classified as Likely benign.
Frequency
Consequence
NM_000141.5 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FGFR2 | NM_000141.5 | c.940G>T | p.Ala314Ser | missense_variant, splice_region_variant | 8/18 | ENST00000358487.10 | |
FGFR2 | NM_022970.4 | c.1087+1219G>T | intron_variant | ENST00000457416.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FGFR2 | ENST00000358487.10 | c.940G>T | p.Ala314Ser | missense_variant, splice_region_variant | 8/18 | 1 | NM_000141.5 | A2 | |
FGFR2 | ENST00000457416.7 | c.1087+1219G>T | intron_variant | 1 | NM_022970.4 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
FGFR2-related craniosynostosis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 24, 2021 | This sequence change replaces alanine with serine at codon 314 of the FGFR2 protein (p.Ala314Ser). The alanine residue is weakly conserved and there is a moderate physicochemical difference between alanine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected with clinical features of FGFR2-related disorder (Invitae). This variant has also been reported in an individual with craniosynostosis (PMID: 9521581) and it has been reported in 2 individuals with Pfeiffer syndrome (PMID: 7795583). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 24, 2020 | Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25525159, 15565658, 21367659, 29230096, 10951518, 9521581, 8298735, 7795583, 8528214) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at