rs72549296

chr4-54738431-T-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000222.3(KIT):c.2805T>A(p.Ile935=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00233 in 1,614,032 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. I935I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0017 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (9 hom.)
• Consequence: KIT NM_000222.3 splice_region, synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 0.494

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 4-54738431-T-A is Benign according to our data. Variant chr4-54738431-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 221133.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54738431-T-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.494 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0024 (3502/1461816) while in subpopulation MID AF= 0.00659 (38/5766). AF 95% confidence interval is 0.00494. There are 9 homozygotes in gnomad4_exome. There are 1813 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 264 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIT	NM_000222.3	c.2805T>A	p.Ile935=	splice_region_variant, synonymous_variant	21/21	ENST00000288135.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIT	ENST00000288135.6	c.2805T>A	p.Ile935=	splice_region_variant, synonymous_variant	21/21	1	NM_000222.3	P4

Frequencies

GnomAD3 genomes AF: 0.00174 AC: 264 AN: 152098 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00241

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00230 AC: 575 AN: 250312 Hom.: 3 AF XY: 0.00240 AC XY: 325 AN XY: 135426

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00214

Gnomad ASJ exome AF: 0.00665

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00189

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00301

Gnomad OTH exome AF: 0.00392

GnomAD4 exome AF: 0.00240 AC: 3502 AN: 1461816 Hom.: 9 Cov.: 31 AF XY: 0.00249 AC XY: 1813 AN XY: 727214

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.00226

Gnomad4 ASJ exome AF: 0.00773

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00180

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.00254

Gnomad4 OTH exome AF: 0.00265

GnomAD4 genome AF: 0.00173 AC: 264 AN: 152216 Hom.: 1 Cov.: 32 AF XY: 0.00160 AC XY: 119 AN XY: 74422

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.00242

Gnomad4 ASJ AF: 0.00663

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00241

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00274 Hom.: 0

Bravo AF: 0.00199

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00474

EpiControl AF: 0.00504

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 17, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 04, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	KIT: BP4, BP7, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Gastrointestinal stromal tumor Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 07, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 28, 2018	This alteration is classified as likely 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. -

Mastocytosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 19, 2021

- -

KIT-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 18, 2021

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Piebaldism Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
Cadd	Benign	8.5
Dann	Benign	0.65

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: rs72549296; hg19: chr4-55604597; COSMIC: COSV55422077;