chr4-54686164-T-C

Variant names:

• chr4-54686164-T-C
• rs13135792
• NM_000222.3:c.68-9348T>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.68-9348T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.26 in 152,106 control chromosomes in the GnomAD database, including 6,348 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 0.26 (6348 hom., cov: 32)
• Consequence: KIT NM_000222.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.350
• Publications: 6 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=-0.84).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.369 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIT	NM_000222.3	c.68-9348T>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.68-9348T>C		intron_variant	Intron 1 of 20	1	NM_000222.3	ENSP00000288135.6

Frequencies

GnomAD3 genomes AF: 0.261 AC: 39598 AN: 151988 Hom.: 6351 Cov.: 32

Gnomad AFR AF: 0.0786

Gnomad AMI AF: 0.435

Gnomad AMR AF: 0.377

Gnomad ASJ AF: 0.263

Gnomad EAS AF: 0.0949

Gnomad SAS AF: 0.235

Gnomad FIN AF: 0.319

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.347

Gnomad OTH AF: 0.291

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

GnomAD4 genome AF: 0.260 AC: 39599 AN: 152106 Hom.: 6348 Cov.: 32 AF XY: 0.260 AC XY: 19319 AN XY: 74346

African (AFR) AF: 0.0785 AC: 3259 AN: 41534

American (AMR) AF: 0.378 AC: 5763 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.263 AC: 913 AN: 3472

East Asian (EAS) AF: 0.0950 AC: 491 AN: 5170

South Asian (SAS) AF: 0.234 AC: 1129 AN: 4818

European-Finnish (FIN) AF: 0.319 AC: 3371 AN: 10564

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.347 AC: 23607 AN: 67966

Other (OTH) AF: 0.288 AC: 608 AN: 2112

Alfa AF: 0.325 Hom.: 14280

Bravo AF: 0.259

Asia WGS AF: 0.153 AC: 536 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	11
DANN	Benign	0.84
PhyloP100		0.35
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: rs13135792; hg19: chr4-55552330;