rs3822214

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1PP2BP4_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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M541T) has been classified as Uncertain significance.

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

Publications

245 publications found

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 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

KIT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 22 uncertain in NM_000222.3

PP2

Missense variant in the KIT gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 54 curated pathogenic missense variants (we use a threshold of 10). The gene has 7 curated benign missense variants. Gene score misZ: 2.5806 (below the threshold of 3.09). Trascript score misZ: 4.1549 (above the threshold of 3.09). GenCC associations: The gene is linked to cutaneous mastocytosis, gastrointestinal stromal tumor, mastocytosis, piebaldism.

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 Benign/Likely_benign. ClinVar VariationId is 41599.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
KIT	NM_000222.3 link	c.1621A>C	p.Met541Leu	missense_variant	Exon 10 of 21	ENST00000288135.6	NP_000213.1	P10721-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIT	ENST00000288135.6 link	c.1621A>C	p.Met541Leu	missense_variant	Exon 10 of 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

GnomAD2 exomes

AF:

0.0771

AC:

19379

AN:

251206

AF XY:

0.0799

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 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

African (AFR)

AF:

0.0609

AC:

2040

AN:

33474

American (AMR)

AF:

0.0505

AC:

2259

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0978

AC:

2556

AN:

26134

East Asian (EAS)

AF:

0.0487

AC:

1933

AN:

39694

South Asian (SAS)

AF:

0.0773

AC:

6669

AN:

86248

European-Finnish (FIN)

AF:

0.0461

AC:

2462

AN:

53420

Middle Eastern (MID)

AF:

0.0791

AC:

456

AN:

5766

European-Non Finnish (NFE)

AF:

0.106

AC:

117931

AN:

1111776

Other (OTH)

AF:

0.0955

AC:

5769

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

7302

14603

21905

29206

36508

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4356

8712

13068

17424

21780

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0772

AC:

11750

AN:

152264

Hom.:

506

Cov.:

AF XY:

0.0726

AC XY:

5405

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.0593

AC:

2463

AN:

41542

American (AMR)

AF:

0.0662

AC:

1012

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0925

AC:

321

AN:

3472

East Asian (EAS)

AF:

0.0488

AC:

253

AN:

5184

South Asian (SAS)

AF:

0.0742

AC:

358

AN:

4826

European-Finnish (FIN)

AF:

0.0360

AC:

382

AN:

10612

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0991

AC:

6740

AN:

68014

Other (OTH)

AF:

0.0833

AC:

176

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

563

1126

1689

2252

2815

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

288

432

576

720

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0909

Hom.:

2686

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

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

not provided

Benign:3

Jul 13, 2012

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:research

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 22, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 27153395, 18795925, 24728327, 22703879) -

Gastrointestinal stromal tumor

Benign:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Lip and oral cavity carcinoma

Pathogenic:1

Apr 30, 2019

Institute of Medical Sciences, Banaras Hindu University

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Mastocytosis

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Piebaldism

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hereditary cancer-predisposing syndrome

Benign:1

May 08, 2019

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

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

PhyloP100

1.0

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

Mutation Taster

=39/40

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over