4-54733155-A-T

Position:

chr4-54733155-A-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP2PP3_StrongPP5

The ENST00000288135.6(KIT):c.2447A>T(p.Asp816Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,592 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. D816I) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

KIT
ENST00000288135.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:4O:1

Conservation

PhyloP100: 9.22

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]

KIT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in ENST00000288135.6

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr4-54733154-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 13863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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). GenCC has associacion of gene with piebaldism, gastrointestinal stromal tumor, mastocytosis, cutaneous mastocytosis.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.983

PP5

Variant 4-54733155-A-T is Pathogenic according to our data. Variant chr4-54733155-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 13852.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Uncertain_significance=4}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIT	NM_000222.3 linkuse as main transcript	c.2447A>T	p.Asp816Val	missense_variant	17/21	ENST00000288135.6	NP_000213.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIT	ENST00000288135.6 linkuse as main transcript	c.2447A>T	p.Asp816Val	missense_variant	17/21	1	NM_000222.3	ENSP00000288135	P4	P10721-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1460592

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726630

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000468

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6Uncertain:4Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cutaneous mastocytosis

Pathogenic:2Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Aug 31, 2021	ACMG classification criteria: PS3 supporting, PM2 moderate, PP3 supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense c.2447A>T p.Asp816Val variant in KIT gene has been reported repviously as the most common somatic variant causing systemic mastocytosis Ke et al. 2016; Nedoszytko et al. 2021. Experimental studies show that this variant leads to an ligand-independent activation and it gains extra activity via different signaling pathways from that of wild-type KIT Ke et al. 2016. The p.Asp816Val variant is reported with an allele frequency of 0% i.e. no high-confidence genotypes in the gnomAD exomes database and is novel not in any individuals in 1000 Genomes database. The frequency data for this variant in gnomAD exomes database is considered unreliable, as metrics indicate poor data quality at this position. This variant has been reported to the ClinVar database Uncertain Significance / Likely Pathogenic / Pathogenic. The amino acid change p.Asp816Val in KIT is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Asp at position 816 is changed to a Val changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 15, 2001	- -

Gastrointestinal stromal tumor

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 01, 2022	This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 816 of the KIT protein (p.Asp816Val). This variant is not present in population databases (gnomAD no frequency). This variant is the most common somatic change in mastocytosis (PMID: 27777718, 26158763). While this variant has been reported in the literature, it has not been reported in the germline of individuals with KIT-related conditions. ClinVar contains an entry for this variant (Variation ID: 13852). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this variant leads to a gain-of-function of the KIT protein, causing ligand-independent signaling activation as well as oncogenic transformation in vitro (PMID: 27777718, 26158763). In addition, transgenic mice expressing this variant (D816V) show abnormal mast cell proliferation and recapitulate human mastocytosis (PMID: 16352739). However, the clinical significance of the functional impact in the germline is uncertain. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 28, 2024	- -

MAST CELL LEUKEMIA, SOMATIC

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 15, 2001

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Clinical Genetics and Genomics, Karolinska University Hospital

Nov 24, 2014

- -

MASTOCYTOSIS, SYSTEMIC, SOMATIC

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 15, 2001

- -

MASTOCYTOSIS WITH ASSOCIATED HEMATOLOGIC DISORDER, SOMATIC

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 15, 2001

- -

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 12, 2020

The p.D816V variant (also known as c.2447A>T), located in coding exon 17 of the KIT gene, results from an A to T substitution at nucleotide position 2447. The aspartic acid at codon 816 is replaced by valine, an amino acid with highly dissimilar properties. This variant is the most common somatic alteration reported in adults with acquired mastocytosis (Arock M et al. Leukemia 2015 Jun;29(6):1223-32; Orfao A et al. Br. J. Haematol. 2007 Jul;138(1):12-30; Nagata H et al. Proc. Natl. Acad. Sci. U.S.A. 1995 Nov;92(23):10560-4; Baird J et al. Curr Hematol Malig Rep 2018 10;13(5):407-416). Functional studies have demonstrated that p.D816V leads to constitutive activation of KIT (Foster R et al. J. Mol. Graph. Model. 2004 Oct;23(2):139-52; Nagata et al). To our knowledge, p.D816V has not yet been identified as a germline alteration and has not been established to confer increased risk of familial gastrointestinal stromal tumors (GIST). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration in germline carriers remains unclear. -

Dysgerminoma

Other:1

other, no assertion criteria provided

clinical testing

Donald Williams Parsons Laboratory, Baylor College of Medicine

May 01, 2016

- 2: Mutations in members of targetable cancer pathways, gene families, or functional groups, regardless of tumor type;

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.80

.;D

Eigen

Uncertain

0.65

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Uncertain

0.30

MutationAssessor

Benign

0.095

.;N

MutationTaster

Benign

1.0

A;A

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-7.5

D;D

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;D

Vest4

0.97

MutPred

0.89

.;Gain of MoRF binding (P = 0.0494);

MVP

0.99

MPC

1.6

ClinPred

1.0

GERP RS

5.6

Varity_R

0.95

gMVP

0.92

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over