rs72550822

Positions:

• chr4-54727265-G-A
• chr4-54727265-G-C
• chr4-54727265-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS2

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:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00097 (1 hom.)
• Consequence: KIT NM_000222.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:8 O:1
• Conservation: PhyloP100: 5.21

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• PP2: Missense variant where missense usually causes diseases, KIT
• BP4: Computational evidence support a benign effect (MetaRNN=0.017944992).
• BP6: Variant 4-54727265-G-A is Benign according to our data. Variant chr4-54727265-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 134621.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, not_provided=1, Likely_benign=6, Benign=1}. Variant chr4-54727265-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 179 AD gene.

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: 177 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000999

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000549 AC: 138 AN: 251244 Hom.: 1 AF XY: 0.000567 AC XY: 77 AN XY: 135776

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.000578

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000837

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000967 AC: 1413 AN: 1461832 Hom.: 1 Cov.: 32 AF XY: 0.000936 AC XY: 681 AN XY: 727214

Gnomad4 AFR exome AF: 0.00188

Gnomad4 AMR exome AF: 0.000537

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00113

Gnomad4 OTH exome AF: 0.00104

GnomAD4 genome AF: 0.00118 AC: 179 AN: 152312 Hom.: 0 Cov.: 32 AF XY: 0.00126 AC XY: 94 AN XY: 74468

Gnomad4 AFR AF: 0.00197

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000999

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00110 Hom.: 1

Bravo AF: 0.00118

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000552 AC: 67

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.000830

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:8 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign: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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	20
DANN	Benign	0.75
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.018	T;T
MetaSVM	Benign	-0.75	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.31	N;N
REVEL	Uncertain	0.30
Sift	Benign	0.39	T;T
Sift4G	Benign	0.76	T;T
Polyphen		0.45	P;B
Vest4		0.075
MVP		0.70
MPC		0.37
ClinPred		0.017	T
GERP RS		5.9
Varity_R		0.045
gMVP		0.48

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

Other links and lift over

dbSNP: rs72550822; hg19: chr4-55593431; COSMIC: COSV55396593; COSMIC: COSV55396593;