4-54738513-A-G
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBS1_SupportingBS2
The NM_000222.3(KIT):c.2887A>G(p.Thr963Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000123 in 1,461,844 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_000222.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251304Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135808
GnomAD4 exome AF: 0.0000123 AC: 18AN: 1461844Hom.: 1 Cov.: 31 AF XY: 0.0000110 AC XY: 8AN XY: 727228
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Gastrointestinal stromal tumor Uncertain:2
This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 963 of the KIT protein (p.Thr963Ala). This variant is present in population databases (rs773709702, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with KIT-related conditions. ClinVar contains an entry for this variant (Variation ID: 409774). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. -
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Acute myeloid leukemia;C0024899:Mastocytosis;C0080024:Piebaldism;C0153594:Malignant tumor of testis;C0238198:Gastrointestinal stromal tumor Uncertain:1
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not provided Uncertain:1
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Hereditary cancer-predisposing syndrome Uncertain:1
The p.T963A variant (also known as c.2887A>G), located in coding exon 21 of the KIT gene, results from an A to G substitution at nucleotide position 2887. The threonine at codon 963 is replaced by alanine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at