chr4-54716231-C-T

Position:

• chr4-54716231-C-T

Variant summary

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

The NM_000222.3(KIT):​c.1231+6692C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 151,988 control chromosomes in the GnomAD database, including 1,344 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 0.11 (1344 hom., cov: 32)
• Consequence: KIT NM_000222.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.143

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=-0.96).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.257 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIT	NM_000222.3	c.1231+6692C>T		intron_variant		ENST00000288135.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIT	ENST00000288135.6	c.1231+6692C>T		intron_variant		1	NM_000222.3	P4

Frequencies

GnomAD3 genomes AF: 0.107 AC: 16236 AN: 151870 Hom.: 1336 Cov.: 32

Gnomad AFR AF: 0.211

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.117

Gnomad ASJ AF: 0.0663

Gnomad EAS AF: 0.268

Gnomad SAS AF: 0.0656

Gnomad FIN AF: 0.0392

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0463

Gnomad OTH AF: 0.0974

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

GnomAD4 genome AF: 0.107 AC: 16283 AN: 151988 Hom.: 1344 Cov.: 32 AF XY: 0.109 AC XY: 8075 AN XY: 74268

Gnomad4 AFR AF: 0.211

Gnomad4 AMR AF: 0.117

Gnomad4 ASJ AF: 0.0663

Gnomad4 EAS AF: 0.268

Gnomad4 SAS AF: 0.0646

Gnomad4 FIN AF: 0.0392

Gnomad4 NFE AF: 0.0463

Gnomad4 OTH AF: 0.0969

Alfa AF: 0.0868 Hom.: 208

Bravo AF: 0.119

Asia WGS AF: 0.153 AC: 534 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	1.8
DANN	Benign	0.67

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: rs17084687; hg19: chr4-55582397;