4-54727315-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000222.3(KIT):​c.1638A>G​(p.Lys546Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0271 in 1,613,900 control chromosomes in the GnomAD database, including 716 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.023 ( 54 hom., cov: 33)
Exomes 𝑓: 0.027 ( 662 hom. )

Consequence

KIT
NM_000222.3 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 1.77
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.59).
BP6
Variant 4-54727315-A-G is Benign according to our data. Variant chr4-54727315-A-G is described in ClinVar as [Benign]. Clinvar id is 255569.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54727315-A-G is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=1.77 with no splicing effect.
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0233 (3548/152338) while in subpopulation EAS AF= 0.0487 (253/5190). AF 95% confidence interval is 0.0438. There are 54 homozygotes in gnomad4. There are 1723 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 3548 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KITNM_000222.3 linkc.1638A>G p.Lys546Lys synonymous_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
KITENST00000288135.6 linkc.1638A>G p.Lys546Lys synonymous_variant Exon 10 of 21 1 NM_000222.3 ENSP00000288135.6 P10721-1

Frequencies

GnomAD3 genomes
AF:
0.0233
AC:
3549
AN:
152220
Hom.:
54
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00523
Gnomad AMI
AF:
0.0625
Gnomad AMR
AF:
0.0182
Gnomad ASJ
AF:
0.0755
Gnomad EAS
AF:
0.0484
Gnomad SAS
AF:
0.0333
Gnomad FIN
AF:
0.0163
Gnomad MID
AF:
0.0190
Gnomad NFE
AF:
0.0307
Gnomad OTH
AF:
0.0272
GnomAD3 exomes
AF:
0.0275
AC:
6895
AN:
251176
Hom.:
140
AF XY:
0.0286
AC XY:
3883
AN XY:
135744
show subpopulations
Gnomad AFR exome
AF:
0.00547
Gnomad AMR exome
AF:
0.00900
Gnomad ASJ exome
AF:
0.0669
Gnomad EAS exome
AF:
0.0492
Gnomad SAS exome
AF:
0.0328
Gnomad FIN exome
AF:
0.0181
Gnomad NFE exome
AF:
0.0295
Gnomad OTH exome
AF:
0.0283
GnomAD4 exome
AF:
0.0275
AC:
40150
AN:
1461562
Hom.:
662
Cov.:
33
AF XY:
0.0282
AC XY:
20537
AN XY:
727090
show subpopulations
Gnomad4 AFR exome
AF:
0.00370
Gnomad4 AMR exome
AF:
0.0102
Gnomad4 ASJ exome
AF:
0.0681
Gnomad4 EAS exome
AF:
0.0392
Gnomad4 SAS exome
AF:
0.0332
Gnomad4 FIN exome
AF:
0.0175
Gnomad4 NFE exome
AF:
0.0275
Gnomad4 OTH exome
AF:
0.0282
GnomAD4 genome
AF:
0.0233
AC:
3548
AN:
152338
Hom.:
54
Cov.:
33
AF XY:
0.0231
AC XY:
1723
AN XY:
74488
show subpopulations
Gnomad4 AFR
AF:
0.00519
Gnomad4 AMR
AF:
0.0182
Gnomad4 ASJ
AF:
0.0755
Gnomad4 EAS
AF:
0.0487
Gnomad4 SAS
AF:
0.0330
Gnomad4 FIN
AF:
0.0163
Gnomad4 NFE
AF:
0.0307
Gnomad4 OTH
AF:
0.0279
Alfa
AF:
0.0305
Hom.:
52
Bravo
AF:
0.0227
Asia WGS
AF:
0.0460
AC:
160
AN:
3478
EpiCase
AF:
0.0326
EpiControl
AF:
0.0281

ClinVar

Significance: Benign
Submissions summary: Benign:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:3
-
Genome Diagnostics Laboratory, Amsterdam University Medical Center
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

- -

-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

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

- -

Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Jul 07, 2023
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Benign:2
Aug 01, 2019
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Mastocytosis Benign:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Piebaldism Benign:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

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
BayesDel_noAF
Benign
-0.59
CADD
Benign
6.3
DANN
Benign
0.42

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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.

Other links and lift over

dbSNP: rs55986963; hg19: chr4-55593481; COSMIC: COSV55391099; COSMIC: COSV55391099; API