chr4-54728065-G-T

Position:

• chr4-54728065-G-T

Variant summary

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

The NM_000222.3(KIT):​c.1934G>T​(p.Ser645Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,082 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: KIT NM_000222.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.93

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). The gene has 54 curated pathogenic missense variants (we use a threshold of 10). The gene has 7 curated benign missense variants. GenCC has associacion of the 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.1934G>T	p.Ser645Ile	missense_variant	13/21	ENST00000288135.6	NP_000213.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIT	ENST00000288135.6	c.1934G>T	p.Ser645Ile	missense_variant	13/21	1	NM_000222.3	ENSP00000288135.6

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152082 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.000478

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152082 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74284

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000478

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	.;D
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.57	D;D
MetaSVM	Uncertain	0.30	D
MutationAssessor	Benign	0.82	.;L
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-4.3	D;D
REVEL	Uncertain	0.53
Sift	Benign	0.072	T;T
Sift4G	Benign	0.096	T;T
Polyphen		0.99	D;D
Vest4		0.41
MutPred		0.65		.;Gain of ubiquitination at K642 (P = 0.0686);
MVP		0.71
MPC		1.4
ClinPred		0.99	D
GERP RS		6.1
Varity_R		0.68
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1060502566; hg19: chr4-55594231;