4-54723696-G-C
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2
The NM_000222.3(KIT):c.1344G>C(p.Gln448His) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000504 in 1,585,994 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_000222.3 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152226Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251366Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135856
GnomAD4 exome AF: 0.00000419 AC: 6AN: 1433650Hom.: 0 Cov.: 25 AF XY: 0.00000699 AC XY: 5AN XY: 715098
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152344Hom.: 0 Cov.: 32 AF XY: 0.0000268 AC XY: 2AN XY: 74492
ClinVar
Submissions by phenotype
Gastrointestinal stromal tumor Uncertain:2
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This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 448 of the KIT protein (p.Gln448His). This variant is present in population databases (rs542718349, gnomAD 0.006%). 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: 458867). 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 disruptive. 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. -
Acute myeloid leukemia;C0080024:Piebaldism;C0238198:Gastrointestinal stromal tumor;C1136033:Cutaneous mastocytosis;C1336708:Germ cell tumor of testis Uncertain:1
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Hereditary cancer-predisposing syndrome Uncertain:1
The p.Q448H variant (also known as c.1344G>C), located in coding exon 8 of the KIT gene, results from a G to C substitution at nucleotide position 1344. The glutamine at codon 448 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at