rs773723931

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000222.3(KIT):c.1137A>G(p.Leu379Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000391 in 1,612,098 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L379L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000041 ( 0 hom. )

Consequence

KIT
NM_000222.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.376

Publications

2 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 4-54709445-A-G is Benign according to our data. Variant chr4-54709445-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 415815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54709445-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 415815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54709445-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 415815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54709445-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 415815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54709445-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 415815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54709445-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 415815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54709445-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 415815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54709445-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 415815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54709445-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 415815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54709445-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 415815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54709445-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 415815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54709445-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 415815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54709445-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 415815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54709445-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 415815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54709445-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 415815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54709445-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 415815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54709445-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 415815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54709445-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 415815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54709445-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 415815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54709445-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 415815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54709445-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 415815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54709445-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 415815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54709445-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 415815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.376 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.0000411 (60/1459876) while in subpopulation AMR AF = 0.00132 (59/44722). AF 95% confidence interval is 0.00105. There are 0 homozygotes in GnomAdExome4. There are 27 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High AC in GnomAdExome4 at 60 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIT	NM_000222.3 link	c.1137A>G	p.Leu379Leu	synonymous_variant	Exon 7 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.1137A>G	p.Leu379Leu	synonymous_variant	Exon 7 of 21	1	NM_000222.3	ENSP00000288135.6		P10721-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

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:

0.000235

AC:

AN:

251444

AF XY:

0.000191

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00153

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000978

GnomAD4 exome

AF:

0.0000411

AC:

AN:

1459876

Hom.:

Cov.:

AF XY:

0.0000372

AC XY:

AN XY:

726406

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33440

American (AMR)

AF:

0.00132

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39674

South Asian (SAS)

AF:

0.00

AC:

AN:

86226

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

9.01e-7

AC:

AN:

1110188

Other (OTH)

AF:

0.00

AC:

AN:

60320

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

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:

0.0000197

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41458

American (AMR)

AF:

0.000196

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.00

Hom.:

Bravo

AF:

0.0000642

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Gastrointestinal stromal tumor

Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:1

Mar 30, 2019

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

BayesDel_noAF

Benign

-0.79

CADD

Benign

1.9

(source)

DANN

Benign

0.41

PhyloP100

-0.38

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