rs1005438

Variant names:

• chr4-54657771-G-A
• rs1005438
• ENST00000689994.1:c.-444+416G>A

Your query was ambiguous. Multiple possible variants found:

• chr4-54657771-G-A
• chr4-54657771-G-C
• chr4-54657771-G-T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 1 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 -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 rank	MANE	Protein	UniProt
KIT	NM_000222.3	c.-244G>A		upstream_gene_variant		ENST00000288135.6	NP_000213.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIT	ENST00000288135.6	c.-244G>A		upstream_gene_variant		1	NM_000222.3	ENSP00000288135.6

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

African (AFR) AF: 0.0980 AC: 744 AN: 7588

American (AMR) AF: 0.443 AC: 6003 AN: 13538

Ashkenazi Jewish (ASJ) AF: 0.309 AC: 3565 AN: 11552

East Asian (EAS) AF: 0.131 AC: 3337 AN: 25410

South Asian (SAS) AF: 0.263 AC: 10424 AN: 39608

European-Finnish (FIN) AF: 0.351 AC: 9607 AN: 27354

Middle Eastern (MID) AF: 0.226 AC: 392 AN: 1732

European-Non Finnish (NFE) AF: 0.368 AC: 88660 AN: 240974

Other (OTH) AF: 0.326 AC: 7460 AN: 22886

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

African (AFR) AF: 0.102 AC: 4221 AN: 41480

American (AMR) AF: 0.402 AC: 6135 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.307 AC: 1063 AN: 3466

East Asian (EAS) AF: 0.133 AC: 668 AN: 5032

South Asian (SAS) AF: 0.243 AC: 1170 AN: 4814

European-Finnish (FIN) AF: 0.348 AC: 3669 AN: 10558

Middle Eastern (MID) AF: 0.197 AC: 58 AN: 294

European-Non Finnish (NFE) AF: 0.369 AC: 24981 AN: 67748

Other (OTH) AF: 0.286 AC: 602 AN: 2108

Alfa AF: 0.289 Hom.: 1986

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

Jun 22, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	2.6
DANN	Benign	0.97
PhyloP100		-0.90
PromoterAI		-0.090	Neutral

Splicing

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

Other links and lift over

dbSNP: rs1005438; hg19: chr4-55523938;