rs2237025

Positions:

• chr4-54675713-T-C
• chr4-54675713-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000222.3(KIT):​c.67+17632T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.597 in 152,008 control chromosomes in the GnomAD database, including 27,864 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.60 (27864 hom., cov: 32)
• Consequence: KIT NM_000222.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0430

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.734 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIT	NM_000222.3	c.67+17632T>C		intron_variant		ENST00000288135.6	NP_000213.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIT	ENST00000288135.6	c.67+17632T>C		intron_variant		1	NM_000222.3	ENSP00000288135	P4

Frequencies

GnomAD3 genomes AF: 0.597 AC: 90658 AN: 151890 Hom.: 27822 Cov.: 32

Gnomad AFR AF: 0.741

Gnomad AMI AF: 0.589

Gnomad AMR AF: 0.591

Gnomad ASJ AF: 0.487

Gnomad EAS AF: 0.349

Gnomad SAS AF: 0.516

Gnomad FIN AF: 0.526

Gnomad MID AF: 0.434

Gnomad NFE AF: 0.553

Gnomad OTH AF: 0.578

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.597 AC: 90754 AN: 152008 Hom.: 27864 Cov.: 32 AF XY: 0.594 AC XY: 44124 AN XY: 74298

Gnomad4 AFR AF: 0.741

Gnomad4 AMR AF: 0.591

Gnomad4 ASJ AF: 0.487

Gnomad4 EAS AF: 0.350

Gnomad4 SAS AF: 0.516

Gnomad4 FIN AF: 0.526

Gnomad4 NFE AF: 0.553

Gnomad4 OTH AF: 0.579

Alfa AF: 0.570 Hom.: 5065

Bravo AF: 0.608

Asia WGS AF: 0.490 AC: 1703 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.2
DANN	Benign	0.59

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: rs2237025; hg19: chr4-55541879;