chr4-54728055-A-G

Variant names:

• chr4-54728055-A-G
• rs121913512
• NM_000222.3:c.1924A>G

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_000222.3(KIT):​c.1924A>G​(p.Lys642Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K642Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KIT NM_000222.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 9.23
• Publications: 359 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.95
• PP5: Variant 4-54728055-A-G is Pathogenic according to our data. Variant chr4-54728055-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 13866.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIT	NM_000222.3	MANE Select	c.1924A>G	p.Lys642Glu	missense	Exon 13 of 21	NP_000213.1
	KIT	NM_001385284.1		c.1927A>G	p.Lys643Glu	missense	Exon 13 of 21	NP_001372213.1
	KIT	NM_001385290.1		c.1927A>G	p.Lys643Glu	missense	Exon 13 of 21	NP_001372219.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIT	ENST00000288135.6	TSL:1 MANE Select	c.1924A>G	p.Lys642Glu	missense	Exon 13 of 21	ENSP00000288135.6
	KIT	ENST00000412167.7	TSL:1	c.1915A>G	p.Lys639Glu	missense	Exon 13 of 21	ENSP00000390987.3
	KIT	ENST00000687109.1		c.1927A>G	p.Lys643Glu	missense	Exon 13 of 21	ENSP00000509371.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Gastrointestinal stromal tumor Pathogenic:2 Other:1

National Institute of Cancer Research, National Health Research Institutes

Significance:

Review Status: no assertion criteria provided

Collection Method: research

the literature

Oct 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 642 of the KIT protein (p.Lys642Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with familial gastrointestinal stromal tumors (PMID: 17824795, 22626674, 23648119, 29098070). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13866). 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. Experimental studies have shown that this missense change affects KIT function (PMID: 11073817). For these reasons, this variant has been classified as Pathogenic.

Feb 04, 2025

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The following ACMG criteria have been used in classification: PM2_SUP; PP3; PS4; PP1; PS3

Gastrointestinal stromal tumor, familial Pathogenic:1

Nov 01, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.79	D
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.29	D
MutationAssessor	Benign	0.11	N
PhyloP100		9.2
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.82		Loss of ubiquitination at K642 (P = 0.0167)
MVP		0.98
MPC		1.6
ClinPred		1.0	D
GERP RS		6.1
Varity_R		0.97
gMVP		0.92
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs121913512; hg19: chr4-55594221; COSMIC: COSV55387507; COSMIC: COSV55387507;