rs2703488

Variant names:

• chr4-54688165-T-C
• rs2703488
• NM_000222.3:c.68-7347T>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.68-7347T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.503 in 152,010 control chromosomes in the GnomAD database, including 19,651 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 0.50 (19651 hom., cov: 32)
• Consequence: KIT NM_000222.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.124
• Publications: 2 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=-0.83).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.594 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIT	NM_000222.3	c.68-7347T>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.68-7347T>C		intron_variant	Intron 1 of 20	1	NM_000222.3	ENSP00000288135.6

Frequencies

GnomAD3 genomes AF: 0.503 AC: 76378 AN: 151892 Hom.: 19615 Cov.: 32

Gnomad AFR AF: 0.600

Gnomad AMI AF: 0.498

Gnomad AMR AF: 0.524

Gnomad ASJ AF: 0.417

Gnomad EAS AF: 0.224

Gnomad SAS AF: 0.408

Gnomad FIN AF: 0.432

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.483

Gnomad OTH AF: 0.507

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

GnomAD4 genome AF: 0.503 AC: 76477 AN: 152010 Hom.: 19651 Cov.: 32 AF XY: 0.499 AC XY: 37100 AN XY: 74316

African (AFR) AF: 0.600 AC: 24890 AN: 41462

American (AMR) AF: 0.524 AC: 8006 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.417 AC: 1446 AN: 3466

East Asian (EAS) AF: 0.225 AC: 1158 AN: 5158

South Asian (SAS) AF: 0.408 AC: 1963 AN: 4812

European-Finnish (FIN) AF: 0.432 AC: 4559 AN: 10564

Middle Eastern (MID) AF: 0.344 AC: 101 AN: 294

European-Non Finnish (NFE) AF: 0.483 AC: 32841 AN: 67976

Other (OTH) AF: 0.504 AC: 1060 AN: 2102

Alfa AF: 0.490 Hom.: 6866

Bravo AF: 0.515

Asia WGS AF: 0.346 AC: 1206 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.3
DANN	Benign	0.67
PhyloP100		0.12
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: rs2703488; hg19: chr4-55554331;