4-54675713-T-C

Variant names:

• chr4-54675713-T-C
• rs2237025
• NM_000222.3:c.67+17632T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 7 publications found

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 Gene-Disease associations (from GenCC):

• gastrointestinal stromal tumor

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Ambry Genetics
• piebaldism

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
• cutaneous mastocytosis

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• mastocytosis

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
KIT	NM_000222.3	c.67+17632T>C		intron_variant	Intron 1 of 20	ENST00000288135.6	NP_000213.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIT	ENST00000288135.6	c.67+17632T>C		intron_variant	Intron 1 of 20	1	NM_000222.3	ENSP00000288135.6

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

African (AFR) AF: 0.741 AC: 30727 AN: 41472

American (AMR) AF: 0.591 AC: 9026 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.487 AC: 1687 AN: 3466

East Asian (EAS) AF: 0.350 AC: 1803 AN: 5152

South Asian (SAS) AF: 0.516 AC: 2484 AN: 4816

European-Finnish (FIN) AF: 0.526 AC: 5552 AN: 10562

Middle Eastern (MID) AF: 0.425 AC: 125 AN: 294

European-Non Finnish (NFE) AF: 0.553 AC: 37591 AN: 67948

Other (OTH) AF: 0.579 AC: 1224 AN: 2114

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
PhyloP100		0.043
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2237025; hg19: chr4-55541879;