4-54727444-T-C

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2PM5PP2PP3_ModeratePP5_Very_Strong

The NM_000222.3(KIT):c.1676T>C(p.Val559Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V559G) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

KIT
NM_000222.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 7.86

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr4-54727444-T-G is described in Lovd as [Likely_pathogenic].

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 piebaldism, gastrointestinal stromal tumor, mastocytosis, cutaneous mastocytosis.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.937

PP5

Variant 4-54727444-T-C is Pathogenic according to our data. Variant chr4-54727444-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIT	NM_000222.3 link	c.1676T>C	p.Val559Ala	missense_variant	Exon 11 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.1676T>C	p.Val559Ala	missense_variant	Exon 11 of 21	1	NM_000222.3	ENSP00000288135.6		P10721-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461800

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cutaneous mastocytosis

Pathogenic:1

Aug 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided

Pathogenic:1

May 22, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24847623, 28074523, 24755198, 27437068, 12960119, 16908931, 18980976, 7530509, 15790786, 16731599, 19812602, 20736294, 21159146, 22357254, 11276010, 17372901, 25157968, 32782703, 9438854, 32716058, 25746950, 23776354, 17255767, 11505412, 16185297, 20952281, 15837988, 11208730) -

Gastrointestinal stromal tumor

Pathogenic:1

Nov 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 559 of the KIT protein (p.Val559Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with gastrointestinal stromal tumor syndrome (PMID: 11208730, 15837988, 24847623). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13865). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Sep 11, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.V559A variant (also known as c.1676T>C), located in coding exon 11 of the KIT gene, results from a T to C substitution at nucleotide position 1676. The valine at codon 559 is replaced by alanine, an amino acid with similar properties. This variant was reported in multiple individuals with features consistent with KIT-related gastrointestinal stromal tumor syndrome (Ambry internal data; Beghini A et al. Cancer, 2001 Aug;92:657-62; Maeyama H et al. Gastroenterology, 2001 Jan;120:210-5; Li FP et al. J Clin Oncol, 2005 Apr;23:2735-43; Adela Avila S et al. Acta Gastroenterol Latinoam, 2014 Mar;44:9-15; Gupta D et al. Int J Dermatol, 2017 Feb;56:195-201). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Gastrointestinal stromal tumor, familial

Pathogenic:1

Aug 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.61

.;D

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.80

T;T

M_CAP

Pathogenic

0.44

MetaRNN

Pathogenic

0.94

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.5

.;M

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-3.6

D;D

REVEL

Pathogenic

0.93

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0040

D;D

Polyphen

1.0

D;D

Vest4

0.86

MutPred

0.75

.;Loss of methylation at K558 (P = 0.0426);

MVP

0.94

MPC

1.4

ClinPred

0.99

GERP RS

6.1

Varity_R

0.73

gMVP

0.87

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over