chr4-54727437-T-G
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP2PP3_Moderate
The NM_000222.3(KIT):c.1669T>G(p.Trp557Gly) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W557C) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000222.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KIT | NM_000222.3 | c.1669T>G | p.Trp557Gly | missense_variant | 11/21 | ENST00000288135.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KIT | ENST00000288135.6 | c.1669T>G | p.Trp557Gly | missense_variant | 11/21 | 1 | NM_000222.3 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 33
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Gastrointestinal stromal tumor Pathogenic:1Uncertain:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 13, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 29, 2022 | 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 disruptive. ClinVar contains an entry for this variant (Variation ID: 376732). This missense change has been observed in individual(s) with clinical features of gastrointestinal stromal tumor syndrome (PMID: 16751810). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 557 of the KIT protein (p.Trp557Gly). Experimental studies have shown that this missense change affects KIT function (PMID: 23567324). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Trp557 amino acid residue in KIT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10680913, 14977822). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at