rs3822214

Positions:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_000222.3(KIT):c.1621A>C(p.Met541Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0953 in 1,613,890 control chromosomes in the GnomAD database, including 7,906 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M541V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.077 ( 506 hom., cov: 32)

Exomes 𝑓: 0.097 ( 7400 hom. )

Consequence

KIT
NM_000222.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:12O:1

Conservation

PhyloP100: 1.03

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 -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KIT. . Gene score misZ: 2.5806 (greater than the threshold 3.09). Trascript score misZ: 4.1549 (greater than threshold 3.09). The gene has 54 curated pathogenic missense variants (we use a threshold of 10). The gene has 7 curated benign missense variants. GenCC has associacion of the gene with piebaldism, gastrointestinal stromal tumor, mastocytosis, cutaneous mastocytosis.

BP4

Computational evidence support a benign effect (MetaRNN=0.0028303266).

BP6

Variant 4-54727298-A-C is Benign according to our data. Variant chr4-54727298-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 41599.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54727298-A-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0971 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIT	NM_000222.3 link	c.1621A>C	p.Met541Leu	missense_variant	10/21	ENST00000288135.6	NP_000213.1	P10721-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIT	ENST00000288135.6 link	c.1621A>C	p.Met541Leu	missense_variant	10/21	1	NM_000222.3	ENSP00000288135.6		P10721-1

Frequencies

GnomAD3 genomes

AF:

0.0772

AC:

11752

AN:

152146

Hom.:

505

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0595

Gnomad AMI

AF:

0.0351

Gnomad AMR

AF:

0.0663

Gnomad ASJ

AF:

0.0925

Gnomad EAS

AF:

0.0487

Gnomad SAS

AF:

0.0747

Gnomad FIN

AF:

0.0360

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0991

Gnomad OTH

AF:

0.0817

GnomAD3 exomes

AF:

0.0771

AC:

19379

AN:

251206

Hom.:

827

AF XY:

0.0799

AC XY:

10846

AN XY:

135752

show subpopulations

Gnomad AFR exome

AF:

0.0603

Gnomad AMR exome

AF:

0.0486

Gnomad ASJ exome

AF:

0.0974

Gnomad EAS exome

AF:

0.0469

Gnomad SAS exome

AF:

0.0759

Gnomad FIN exome

AF:

0.0415

Gnomad NFE exome

AF:

0.0979

Gnomad OTH exome

AF:

0.0879

GnomAD4 exome

AF:

0.0972

AC:

142075

AN:

1461626

Hom.:

7400

Cov.:

AF XY:

0.0967

AC XY:

70320

AN XY:

727146

show subpopulations

Gnomad4 AFR exome

AF:

0.0609

Gnomad4 AMR exome

AF:

0.0505

Gnomad4 ASJ exome

AF:

0.0978

Gnomad4 EAS exome

AF:

0.0487

Gnomad4 SAS exome

AF:

0.0773

Gnomad4 FIN exome

AF:

0.0461

Gnomad4 NFE exome

AF:

0.106

Gnomad4 OTH exome

AF:

0.0955

GnomAD4 genome

AF:

0.0772

AC:

11750

AN:

152264

Hom.:

506

Cov.:

AF XY:

0.0726

AC XY:

5405

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.0593

Gnomad4 AMR

AF:

0.0662

Gnomad4 ASJ

AF:

0.0925

Gnomad4 EAS

AF:

0.0488

Gnomad4 SAS

AF:

0.0742

Gnomad4 FIN

AF:

0.0360

Gnomad4 NFE

AF:

0.0991

Gnomad4 OTH

AF:

0.0833

Alfa

AF:

0.0918

Hom.:

1463

Bravo

AF:

0.0794

TwinsUK

AF:

0.109

AC:

404

ALSPAC

AF:

0.102

AC:

392

ESP6500AA

AF:

0.0635

AC:

280

ESP6500EA

AF:

0.112

AC:

962

ExAC

AF:

0.0789

AC:

9575

Asia WGS

AF:

0.0750

AC:

261

AN:

3478

EpiCase

AF:

0.0994

EpiControl

AF:

0.105

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided

Benign:3

Benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2018	This variant is associated with the following publications: (PMID: 27153395, 18795925, 24728327, 22703879) -

Gastrointestinal stromal tumor

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

Lip and oral cavity carcinoma

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Institute of Medical Sciences, Banaras Hindu University

Apr 30, 2019

- -

Mastocytosis

Benign:1

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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Piebaldism

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

Hereditary cancer-predisposing syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 08, 2019

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.14

CADD

Benign

DANN

Benign

0.49

DEOGEN2

Benign

0.23

.;T

Eigen

Benign

-0.94

Eigen_PC

Benign

-0.78

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.75

T;T

MetaRNN

Benign

0.0028

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.38

.;N

PrimateAI

Benign

0.42

PROVEAN

Benign

0.22

N;N

REVEL

Uncertain

0.42

Sift

Benign

0.80

T;T

Sift4G

Benign

0.81

T;T

Polyphen

0.012

B;B

Vest4

0.45

MutPred

0.14

.;Gain of catalytic residue at M541 (P = 0.0666);

MPC

0.41

ClinPred

0.000031

GERP RS

1.8

Varity_R

0.059

gMVP

0.69

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

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