dbSNP rs115585711: KIT:p.Ala178Thr (chr4-54698478-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_000222.3(KIT):c.532G>A(p.Ala178Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000569 in 1,614,132 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A178S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0031 ( 3 hom., cov: 33)

Exomes 𝑓: 0.00030 ( 2 hom. )

Consequence

KIT
NM_000222.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: -0.00100

Publications

13 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: Ambry Genetics, ClinGen, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
piebaldism
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
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 -12 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=0.0062642395).

BP6

Variant 4-54698478-G-A is Benign according to our data. Variant chr4-54698478-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 161259.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00313 (477/152256) while in subpopulation AFR AF = 0.0111 (460/41552). AF 95% confidence interval is 0.0102. There are 3 homozygotes in GnomAd4. There are 230 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 477 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000222.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KIT	NM_000222.3	MANE Select	c.532G>A	p.Ala178Thr	missense	Exon 3 of 21	NP_000213.1	P10721-1
KIT	NM_001385284.1		c.532G>A	p.Ala178Thr	missense	Exon 3 of 21	NP_001372213.1	A0A8I5KS03
KIT	NM_001385290.1		c.532G>A	p.Ala178Thr	missense	Exon 3 of 21	NP_001372219.1	A0A8I5QKP7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KIT	ENST00000288135.6	TSL:1 MANE Select	c.532G>A	p.Ala178Thr	missense	Exon 3 of 21	ENSP00000288135.6	P10721-1
KIT	ENST00000412167.7	TSL:1	c.532G>A	p.Ala178Thr	missense	Exon 3 of 21	ENSP00000390987.3	A0A8J8Z860
KIT	ENST00000687109.1		c.532G>A	p.Ala178Thr	missense	Exon 3 of 21	ENSP00000509371.1	A0A8I5KS03

Frequencies

GnomAD3 genomes

AF:

0.00314

AC:

477

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0111

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

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:

0.0000882

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.000828

AC:

208

AN:

251154

AF XY:

0.000663

show subpopulations

Gnomad AFR exome

AF:

0.0123

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000302

AC:

442

AN:

1461876

Hom.:

Cov.:

AF XY:

0.000252

AC XY:

183

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.0113

AC:

377

AN:

33478

American (AMR)

AF:

0.000291

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000225

AC:

AN:

1112002

Other (OTH)

AF:

0.000447

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

114

143

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00313

AC:

477

AN:

152256

Hom.:

Cov.:

AF XY:

0.00309

AC XY:

230

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.0111

AC:

460

AN:

41552

American (AMR)

AF:

0.000392

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68024

Other (OTH)

AF:

0.00237

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

107

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.000889

Hom.:

Bravo

AF:

0.00366

ESP6500AA

AF:

0.00999

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000947

AC:

115

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Hereditary cancer-predisposing syndrome (2)

Gastrointestinal stromal tumor (1)

KIT-related disorder (1)

Piebaldism (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.59

CADD

Benign

3.6

(source)

DANN

Benign

0.78

DEOGEN2

Benign

0.24

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.67

MetaRNN

Benign

0.0063

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.54

PhyloP100

-0.0010

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.59

REVEL

Benign

0.093

Sift

Benign

0.70

Sift4G

Benign

0.53

Polyphen

0.0030

Vest4

0.12

MVP

0.36

MPC

0.43

ClinPred

0.0027

GERP RS

-0.81

Varity_R

0.073

gMVP

0.82

Mutation Taster

=89/11

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over