rs72550820

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000222.3(KIT):c.67+4G>A variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0138 in 1,613,756 control chromosomes in the GnomAD database, including 196 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 9 hom., cov: 33)

Exomes 𝑓: 0.014 ( 187 hom. )

Consequence

KIT
NM_000222.3 splice_donor_region, intron

Scores

Splicing: ADA: 0.008197

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 2.26

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BP6

Variant 4-54658085-G-A is Benign according to our data. Variant chr4-54658085-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 221041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54658085-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0101 (1543/152292) while in subpopulation SAS AF= 0.024 (116/4832). AF 95% confidence interval is 0.0205. There are 9 homozygotes in gnomad4. There are 790 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1543 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIT	NM_000222.3 linkuse as main transcript	c.67+4G>A		splice_donor_region_variant, intron_variant		ENST00000288135.6	NP_000213.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIT	ENST00000288135.6 linkuse as main transcript	c.67+4G>A		splice_donor_region_variant, intron_variant		1	NM_000222.3	ENSP00000288135	P4	P10721-1

Frequencies

GnomAD3 genomes

AF:

0.0102

AC:

1546

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00955

Gnomad ASJ

AF:

0.00519

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.0242

Gnomad FIN

AF:

0.00584

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0159

Gnomad OTH

AF:

0.00860

GnomAD3 exomes

AF:

0.0115

AC:

2882

AN:

249620

Hom.:

AF XY:

0.0123

AC XY:

1661

AN XY:

135274

show subpopulations

Gnomad AFR exome

AF:

0.00254

Gnomad AMR exome

AF:

0.00640

Gnomad ASJ exome

AF:

0.00597

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0204

Gnomad FIN exome

AF:

0.00653

Gnomad NFE exome

AF:

0.0154

Gnomad OTH exome

AF:

0.0113

GnomAD4 exome

AF:

0.0141

AC:

20655

AN:

1461464

Hom.:

187

Cov.:

AF XY:

0.0144

AC XY:

10438

AN XY:

727070

show subpopulations

Gnomad4 AFR exome

AF:

0.00203

Gnomad4 AMR exome

AF:

0.00718

Gnomad4 ASJ exome

AF:

0.00655

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0215

Gnomad4 FIN exome

AF:

0.00674

Gnomad4 NFE exome

AF:

0.0153

Gnomad4 OTH exome

AF:

0.0132

GnomAD4 genome

AF:

0.0101

AC:

1543

AN:

152292

Hom.:

Cov.:

AF XY:

0.0106

AC XY:

790

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.00241

Gnomad4 AMR

AF:

0.00954

Gnomad4 ASJ

AF:

0.00519

Gnomad4 EAS

AF:

0.000195

Gnomad4 SAS

AF:

0.0240

Gnomad4 FIN

AF:

0.00584

Gnomad4 NFE

AF:

0.0159

Gnomad4 OTH

AF:

0.00851

Alfa

AF:

0.0105

Hom.:

Bravo

AF:

0.00937

Asia WGS

AF:

0.00722

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 20, 2020	This variant is associated with the following publications: (PMID: 23020152, 27535533, 7529964, 15901127, 22264755) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	KIT: BP4, BS1, BS2 -

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Piebaldism

Benign:2

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. -
Benign, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	-	The heterozygous c.67+4G>A variant in KIT has been reported in an individual with piebaldism (PMID: 7529964) but has also been reported in >2% of South Asian chromosomes and 15 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for autosomal dominant piebaldism. -

Gastrointestinal stromal tumor

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

Hereditary cancer-predisposing syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 26, 2018	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Feb 24, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Benign

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0082

dbscSNV1_RF

Benign

0.62

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over