4-54695695-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_000222.3(KIT):c.251C>T(p.Thr84Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000712 in 1,614,196 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. T84S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000066 ( 0 hom. )

Consequence

KIT
NM_000222.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -1.79

Publications

6 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 -19 ACMG points.

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=0.0052221715).

BP6

Variant 4-54695695-C-T is Benign according to our data. Variant chr4-54695695-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 237265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54695695-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 237265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54695695-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 237265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54695695-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 237265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54695695-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 237265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54695695-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 237265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54695695-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 237265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54695695-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 237265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54695695-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 237265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54695695-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 237265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54695695-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 237265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54695695-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 237265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54695695-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 237265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54695695-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 237265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54695695-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 237265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54695695-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 237265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54695695-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 237265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54695695-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 237265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54695695-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 237265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54695695-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 237265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54695695-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 237265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54695695-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 237265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000125 (19/152316) while in subpopulation EAS AF = 0.00328 (17/5178). AF 95% confidence interval is 0.00209. There are 0 homozygotes in GnomAd4. There are 13 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIT	NM_000222.3 link	c.251C>T	p.Thr84Met	missense_variant	Exon 2 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.251C>T	p.Thr84Met	missense_variant	Exon 2 of 21	1	NM_000222.3	ENSP00000288135.6		P10721-1

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00328

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000318

AC:

AN:

251272

AF XY:

0.000295

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00392

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000657

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.0000523

AC XY:

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.000112

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00207

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1112004

Other (OTH)

AF:

0.0000497

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000125

AC:

AN:

152316

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41570

American (AMR)

AF:

0.000131

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00328

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000114

Hom.:

Bravo

AF:

0.000147

ExAC

AF:

0.000296

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Jun 24, 2016

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

KIT-related disorder

Benign:1

Aug 06, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Gastrointestinal stromal tumor

Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:1

Dec 29, 2018

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.054

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.36

.;T

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.010

LIST_S2

Benign

0.59

T;T

M_CAP

Benign

0.0055

MetaRNN

Benign

0.0052

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

L;L

PhyloP100

-1.8

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.31

N;N

REVEL

Benign

0.030

Sift

Benign

0.12

T;T

Sift4G

Uncertain

0.057

T;T

Polyphen

0.11

B;B

Vest4

0.22

MVP

0.30

MPC

0.51

ClinPred

0.025

GERP RS

-6.1

Varity_R

0.024

gMVP

0.60

Mutation Taster

=85/15

polymorphism

(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