4-54657771-G-A

Position:

• chr4-54657771-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000689994.1(KIT):​c.-444+416G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.319 in 542,312 control chromosomes in the GnomAD database, including 30,436 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.28 (7259 hom., cov: 31)
  • Exomes 𝑓: 0.33 (23177 hom.)
• Consequence: KIT ENST00000689994.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.898

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 4-54657771-G-A is Benign according to our data. Variant chr4-54657771-G-A is described in ClinVar as [Benign]. Clinvar id is 1293458.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.394 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIT	ENST00000689994.1	c.-444+416G>A		intron_variant				ENSP00000509156.1

Frequencies

GnomAD3 genomes AF: 0.283 AC: 42906 AN: 151550 Hom.: 7260 Cov.: 31

Gnomad AFR AF: 0.102

Gnomad AMI AF: 0.381

Gnomad AMR AF: 0.402

Gnomad ASJ AF: 0.307

Gnomad EAS AF: 0.133

Gnomad SAS AF: 0.242

Gnomad FIN AF: 0.348

Gnomad MID AF: 0.201

Gnomad NFE AF: 0.369

Gnomad OTH AF: 0.289

GnomAD4 exome AF: 0.333 AC: 130192 AN: 390642 Hom.: 23177 AF XY: 0.329 AC XY: 68163 AN XY: 206880

Gnomad4 AFR exome AF: 0.0980

Gnomad4 AMR exome AF: 0.443

Gnomad4 ASJ exome AF: 0.309

Gnomad4 EAS exome AF: 0.131

Gnomad4 SAS exome AF: 0.263

Gnomad4 FIN exome AF: 0.351

Gnomad4 NFE exome AF: 0.368

Gnomad4 OTH exome AF: 0.326

GnomAD4 genome AF: 0.283 AC: 42913 AN: 151670 Hom.: 7259 Cov.: 31 AF XY: 0.282 AC XY: 20943 AN XY: 74160

Gnomad4 AFR AF: 0.102

Gnomad4 AMR AF: 0.402

Gnomad4 ASJ AF: 0.307

Gnomad4 EAS AF: 0.133

Gnomad4 SAS AF: 0.243

Gnomad4 FIN AF: 0.348

Gnomad4 NFE AF: 0.369

Gnomad4 OTH AF: 0.286

Alfa AF: 0.296 Hom.: 1782

Bravo AF: 0.280

Asia WGS AF: 0.165 AC: 575 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 22, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	2.6
DANN	Benign	0.97

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1005438; hg19: chr4-55523938;