rs17084733

chr4-54738774-G-Achr4-54738774-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000222.3(KIT):c.*217G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0931 in 632,120 control chromosomes in the GnomAD database, including 3,108 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (860 hom., cov: 32)
  • Exomes 𝑓: 0.091 (2248 hom.)
• Consequence: KIT NM_000222.3 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.752

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 4-54738774-G-A is Benign according to our data. Variant chr4-54738774-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 348959.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.137 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIT	NM_000222.3	c.*217G>A		3_prime_UTR_variant	21/21	ENST00000288135.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIT	ENST00000288135.6	c.*217G>A		3_prime_UTR_variant	21/21	1	NM_000222.3	P4

Frequencies

GnomAD3 genomes AF: 0.101 AC: 15317 AN: 152048 Hom.: 859 Cov.: 32

Gnomad AFR AF: 0.140

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.0758

Gnomad ASJ AF: 0.0925

Gnomad EAS AF: 0.0495

Gnomad SAS AF: 0.0957

Gnomad FIN AF: 0.0361

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0986

Gnomad OTH AF: 0.0956

GnomAD4 exome AF: 0.0906 AC: 43500 AN: 479954 Hom.: 2248 Cov.: 5 AF XY: 0.0912 AC XY: 23172 AN XY: 254056

Gnomad4 AFR exome AF: 0.140

Gnomad4 AMR exome AF: 0.0581

Gnomad4 ASJ exome AF: 0.0975

Gnomad4 EAS exome AF: 0.0490

Gnomad4 SAS exome AF: 0.0947

Gnomad4 FIN exome AF: 0.0484

Gnomad4 NFE exome AF: 0.0983

Gnomad4 OTH exome AF: 0.0997

GnomAD4 genome AF: 0.101 AC: 15323 AN: 152166 Hom.: 860 Cov.: 32 AF XY: 0.0951 AC XY: 7077 AN XY: 74400

Gnomad4 AFR AF: 0.140

Gnomad4 AMR AF: 0.0757

Gnomad4 ASJ AF: 0.0925

Gnomad4 EAS AF: 0.0496

Gnomad4 SAS AF: 0.0952

Gnomad4 FIN AF: 0.0361

Gnomad4 NFE AF: 0.0985

Gnomad4 OTH AF: 0.0974

Alfa AF: 0.0985 Hom.: 750

Bravo AF: 0.106

Asia WGS AF: 0.0920 AC: 319 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Gastrointestinal stromal tumor Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 15, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 22, 2018

This variant is associated with the following publications: (PMID: 30983504, 21119596, 16365291) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	6.6
Dann	Benign	0.60
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs17084733; hg19: chr4-55604940;