chr4-54727895-C-A

Position:

• chr4-54727895-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_000222.3(KIT):​c.1847C>A​(p.Ala616Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KIT NM_000222.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.19

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIT	NM_000222.3	c.1847C>A	p.Ala616Glu	missense_variant	12/21	ENST00000288135.6	NP_000213.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIT	ENST00000288135.6	c.1847C>A	p.Ala616Glu	missense_variant	12/21	1	NM_000222.3	ENSP00000288135	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Gastrointestinal stromal tumor Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 20, 2023

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. 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 disruptive. ClinVar contains an entry for this variant (Variation ID: 1016858). This variant has not been reported in the literature in individuals affected with KIT-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 616 of the KIT protein (p.Ala616Glu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.57	.;D
Eigen	Benign	0.18
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.87	D;T
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.52	D;D
MetaSVM	Uncertain	0.38	D
MutationAssessor	Benign	0.33	.;N
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-2.2	N;N
REVEL	Uncertain	0.47
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.038	D;D
Polyphen		0.97	D;D
Vest4		0.41
MutPred		0.47		.;Loss of sheet (P = 0.0457);
MVP		0.83
MPC		0.96
ClinPred		0.71	D
GERP RS		6.2
Varity_R		0.42
gMVP		0.62

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: rs891140054; hg19: chr4-55594061;