rs72550822
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS2
The NM_000222.3(KIT):c.1588G>A(p.Val530Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000986 in 1,614,144 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V530L) has been classified as Uncertain significance.
Frequency
Consequence
NM_000222.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KIT | NM_000222.3 | c.1588G>A | p.Val530Ile | missense_variant | 10/21 | ENST00000288135.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KIT | ENST00000288135.6 | c.1588G>A | p.Val530Ile | missense_variant | 10/21 | 1 | NM_000222.3 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.00116 AC: 177AN: 152194Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000549 AC: 138AN: 251244Hom.: 1 AF XY: 0.000567 AC XY: 77AN XY: 135776
GnomAD4 exome AF: 0.000967 AC: 1413AN: 1461832Hom.: 1 Cov.: 32 AF XY: 0.000936 AC XY: 681AN XY: 727214
GnomAD4 genome ? AF: 0.00118 AC: 179AN: 152312Hom.: 0 Cov.: 32 AF XY: 0.00126 AC XY: 94AN XY: 74468
ClinVar
Submissions by phenotype
not provided Uncertain:3Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jun 08, 2023 | - - |
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The KIT p.Val526Ile variant has been reported in patients with acute and chronic myeloid leukemia and in an aggressive fibromatosis tumor (Kurtz_2010_PMID:20339585; Kirschner_2015_PMID:25894969; Gari_1999_PMID:10554798; Beghini_2004_PMID:15339674). Functional analysis suggests that this variant may lead to higher sensitivity to Imatinib (Commenga_2013_PMID:16081693). The variant was identified in dbSNP (ID: rs72550822), ClinVar (classified as likely benign by Invitae), and LOVD 3.0, but was not identified in Cosmic. The variant was identified in control databases in 148 of 268108 chromosomes (1 homozygous) at a frequency of 0.000552 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: African in 35 of 23608 chromosomes (freq: 0.001483), European (non-Finnish) in 89 of 117972 chromosomes (freq: 0.000754), Latino in 20 of 35100 chromosomes (freq: 0.00057), Other in 3 of 6692 chromosomes (freq: 0.000448) and Ashkenazi Jewish in 1 of 9858 chromosomes (freq: 0.000101), but was not observed in the East Asian, European (Finnish), or South Asian populations. The p.Val526 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Gastrointestinal stromal tumor Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | May 08, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Likely benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Hereditary cancer-predisposing syndrome Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 29, 2020 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Jun 27, 2021 | - - |
Piebaldism Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | May 08, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Mastocytosis Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | May 08, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. - |
KIT-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 15, 2020 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
not specified Other:1
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at