rs1060502570

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4BS2

The NM_000222.3(KIT):​c.793G>A​(p.Gly265Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000992 in 1,613,448 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

KIT
NM_000222.3 missense

Scores

9
10

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 3.51
Variant links:
Genes affected
KIT (HGNC:6342): (KIT proto-oncogene, receptor tyrosine kinase) This gene encodes a receptor tyrosine kinase. This gene was initially identified as a homolog of the feline sarcoma viral oncogene v-kit and is often referred to as proto-oncogene c-Kit. The canonical form of this glycosylated transmembrane protein has an N-terminal extracellular region with five immunoglobulin-like domains, a transmembrane region, and an intracellular tyrosine kinase domain at the C-terminus. Upon activation by its cytokine ligand, stem cell factor (SCF), this protein phosphorylates multiple intracellular proteins that play a role in in the proliferation, differentiation, migration and apoptosis of many cell types and thereby plays an important role in hematopoiesis, stem cell maintenance, gametogenesis, melanogenesis, and in mast cell development, migration and function. This protein can be a membrane-bound or soluble protein. Mutations in this gene are associated with gastrointestinal stromal tumors, mast cell disease, acute myelogenous leukemia, and piebaldism. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2020]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KIT. . Gene score misZ: 2.5806 (greater than the threshold 3.09). Trascript score misZ: 4.1549 (greater than threshold 3.09). The gene has 54 curated pathogenic missense variants (we use a threshold of 10). The gene has 7 curated benign missense variants. GenCC has associacion of the gene with piebaldism, gastrointestinal stromal tumor, mastocytosis, cutaneous mastocytosis.
BP4
Computational evidence support a benign effect (MetaRNN=0.3847825).
BS2
High AC in GnomAdExome4 at 13 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KITNM_000222.3 linkc.793G>A p.Gly265Ser missense_variant 5/21 ENST00000288135.6 NP_000213.1 P10721-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KITENST00000288135.6 linkc.793G>A p.Gly265Ser missense_variant 5/211 NM_000222.3 ENSP00000288135.6 P10721-1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
151910
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.000288
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000889
AC:
13
AN:
1461538
Hom.:
0
Cov.:
31
AF XY:
0.00000825
AC XY:
6
AN XY:
727058
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.000191
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000720
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
151910
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74166
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.000288
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000889
Hom.:
0

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Gastrointestinal stromal tumor Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsDec 18, 2023- -
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 22, 2023This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 265 of the KIT protein (p.Gly265Ser). 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: 409795). 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. -
Acute myeloid leukemia;C0080024:Piebaldism;C0238198:Gastrointestinal stromal tumor;C1136033:Cutaneous mastocytosis;C1336708:Germ cell tumor of testis Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsApr 30, 2024- -
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJul 15, 2023The p.G265S variant (also known as c.793G>A), located in coding exon 5 of the KIT gene, results from a G to A substitution at nucleotide position 793. The glycine at codon 265 is replaced by serine, an amino acid with 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Uncertain
0.10
D
BayesDel_noAF
Benign
-0.090
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.28
.;T
Eigen
Uncertain
0.49
Eigen_PC
Uncertain
0.53
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.87
D;D
M_CAP
Benign
0.043
D
MetaRNN
Benign
0.38
T;T
MetaSVM
Uncertain
0.15
D
MutationAssessor
Uncertain
2.5
M;M
PrimateAI
Benign
0.41
T
PROVEAN
Benign
-1.7
N;N
REVEL
Uncertain
0.44
Sift
Benign
0.23
T;T
Sift4G
Benign
0.40
T;T
Polyphen
0.93
P;D
Vest4
0.33
MVP
0.84
MPC
0.67
ClinPred
0.86
D
GERP RS
6.0
Varity_R
0.20
gMVP
0.93

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1060502570; hg19: chr4-55569926; COSMIC: COSV55393881; API