rs143179681

chr4-54725996-G-Achr4-54725996-G-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 3P and 8B. PM1 PP2 BP4_Strong BS2

The NM_000222.3(KIT):c.1486G>A(p.Asp496Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000397 in 1,614,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. D496D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: KIT NM_000222.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 1.01

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 Likely_benign. Variant got -5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_000222.3
• PP2: Missense variant where missense usually causes diseases, KIT
• BP4: Computational evidence support a benign effect (MetaRNN=0.047899723).
• BS2: High AC in GnomAd at 28 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIT	NM_000222.3	c.1486G>A	p.Asp496Asn	missense_variant	9/21	ENST00000288135.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIT	ENST00000288135.6	c.1486G>A	p.Asp496Asn	missense_variant	9/21	1	NM_000222.3	P4

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000597 AC: 15 AN: 251182 Hom.: 0 AF XY: 0.0000589 AC XY: 8 AN XY: 135740

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000246 AC: 36 AN: 1461836 Hom.: 0 Cov.: 32 AF XY: 0.0000316 AC XY: 23 AN XY: 727220

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152208 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74350

Gnomad4 AFR AF: 0.000555

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

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

Bravo AF: 0.000128

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000906 AC: 11

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 27, 2023

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 25343854, 25595173, 28327988) -

Gastrointestinal stromal tumor Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 21, 2024

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 496 of the KIT protein (p.Asp496Asn). This variant is present in population databases (rs143179681, gnomAD 0.03%). 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: 409753). 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 asparagine 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. -

KIT-related condition Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 13, 2023

The KIT c.1486G>A variant is predicted to result in the amino acid substitution p.Asp496Asn. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.032% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-55592162-G-A). It has conflicting interpretations of likely benign and uncertain significance (https://preview.ncbi.nlm.nih.gov/clinvar/variation/409753/), At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 25, 2023

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	17
Dann	Benign	0.93
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.69	T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.048	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.1	L;L
MutationTaster	Benign	0.99	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.060	N;N
REVEL	Benign	0.025
Sift	Benign	0.30	T;T
Sift4G	Benign	0.50	T;T
Polyphen		0.0	B;B
Vest4		0.12
MVP		0.63
MPC		0.43
ClinPred		0.063	T
GERP RS		3.3
Varity_R		0.21
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs143179681; hg19: chr4-55592162; COSMIC: COSV55395531; COSMIC: COSV55395531;