chr4-54737209-C-T

Position:

• chr4-54737209-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Strong

The NM_000222.3(KIT):​c.2731C>T​(p.Pro911Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P911H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KIT NM_000222.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 7.91

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_pathogenic. Variant got 7 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIT	NM_000222.3	c.2731C>T	p.Pro911Ser	missense_variant	20/21	ENST00000288135.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIT	ENST00000288135.6	c.2731C>T	p.Pro911Ser	missense_variant	20/21	1	NM_000222.3	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Gastrointestinal stromal tumor Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 09, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 06, 2023	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 911 of the KIT protein (p.Pro911Ser). This variant is not present in population databases (gnomAD no frequency). 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: 528595). 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. 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. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 22, 2023

The p.P911S variant (also known as c.2731C>T), located in coding exon 20 of the KIT gene, results from a C to T substitution at nucleotide position 2731. The proline at codon 911 is replaced by serine, an amino acid with similar properties. This amino acid position is conserved. 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 remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.89	.;D
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Uncertain	2.2	.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-6.3	D;D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.018	D;D
Polyphen		0.97	D;P
Vest4		0.88
MutPred		0.80		.;Gain of glycosylation at T916 (P = 0.0332);
MVP		0.98
MPC		0.96
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.50
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

Other links and lift over

dbSNP: rs1553893575; hg19: chr4-55603375;