Genetic Variant NM_000222.3:c.821C>T (chr4-54703788-C-T) – 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.821C>T(p.Thr274Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00042 in 1,613,308 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 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. T274K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00036 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00043 ( 0 hom. )

Consequence

KIT
NM_000222.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:5

Conservation

PhyloP100: 0.0970

Publications

12 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=0.033516467).

BP6

Variant 4-54703788-C-T is Benign according to our data. Variant chr4-54703788-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 41604.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000355 (54/152068) while in subpopulation NFE AF = 0.000353 (24/67970). AF 95% confidence interval is 0.000243. There are 1 homozygotes in GnomAd4. There are 24 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 54 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.821C>T	p.Thr274Met	missense	Exon 5 of 21	NP_000213.1	P10721-1
KIT	NM_001385284.1		c.824C>T	p.Thr275Met	missense	Exon 5 of 21	NP_001372213.1	A0A8I5KS03
KIT	NM_001385290.1		c.824C>T	p.Thr275Met	missense	Exon 5 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.821C>T	p.Thr274Met	missense	Exon 5 of 21	ENSP00000288135.6	P10721-1
KIT	ENST00000412167.7	TSL:1	c.824C>T	p.Thr275Met	missense	Exon 5 of 21	ENSP00000390987.3	A0A8J8Z860
KIT	ENST00000687109.1		c.824C>T	p.Thr275Met	missense	Exon 5 of 21	ENSP00000509371.1	A0A8I5KS03

Frequencies

GnomAD3 genomes

AF:

0.000355

AC:

AN:

151952

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000353

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000490

AC:

123

AN:

251244

AF XY:

0.000412

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000896

Gnomad ASJ exome

AF:

0.00486

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000299

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.000427

AC:

624

AN:

1461240

Hom.:

Cov.:

AF XY:

0.000406

AC XY:

295

AN XY:

726970

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33460

American (AMR)

AF:

0.000872

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00410

AC:

107

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39676

South Asian (SAS)

AF:

0.00

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.0000562

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000386

AC:

429

AN:

1111458

Other (OTH)

AF:

0.000679

AC:

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

129

161

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.000355

AC:

AN:

152068

Hom.:

Cov.:

AF XY:

0.000323

AC XY:

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.000193

AC:

AN:

41488

American (AMR)

AF:

0.000262

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00490

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10544

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000353

AC:

AN:

67970

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

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:

0.000429

Hom.:

Bravo

AF:

0.000385

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000461

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000491

EpiControl

AF:

0.000474

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Gastrointestinal stromal tumor (2)

Hereditary cancer-predisposing syndrome (2)

Gastrointestinal stromal tumor, familial (1)

Mastocytosis (1)

not specified (1)

Piebaldism (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.035

LIST_S2

Benign

0.78

M_CAP

Benign

0.020

MetaRNN

Benign

0.034

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

PhyloP100

0.097

PrimateAI

Benign

0.27

PROVEAN

Uncertain

-3.7

REVEL

Benign

0.038

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.014

Polyphen

0.94

Vest4

0.14

MVP

0.47

MPC

0.64

ClinPred

0.076

GERP RS

1.2

PromoterAI

-0.012

Neutral

(source)

Varity_R

0.053

gMVP

0.91

Mutation Taster

=98/2

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