4-54723688-A-G
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2BP4_Moderate
The NM_000222.3(KIT):āc.1336A>Gā(p.Thr446Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000436 in 1,605,336 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T446N) has been classified 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 -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KIT | NM_000222.3 | c.1336A>G | p.Thr446Ala | missense_variant | 8/21 | ENST00000288135.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KIT | ENST00000288135.6 | c.1336A>G | p.Thr446Ala | missense_variant | 8/21 | 1 | NM_000222.3 | P4 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152206Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000275 AC: 4AN: 1453130Hom.: 0 Cov.: 28 AF XY: 0.00000415 AC XY: 3AN XY: 723614
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152206Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74350
ClinVar
Submissions by phenotype
Gastrointestinal stromal tumor Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 28, 2023 | This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 446 of the KIT protein (p.Thr446Ala). This variant is present in population databases (no rsID available, gnomAD 0.01%). 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: 528625). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The alanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 29, 2024 | The c.1336A>G (p.T446A) alteration is located in exon 8 (coding exon 8) of the KIT gene. This alteration results from a A to G substitution at nucleotide position 1336, causing the threonine (T) at amino acid position 446 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at