rs772836939

chr4-54698286-C-Achr4-54698286-C-Gchr4-54698286-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_000222.3(KIT):c.340C>A(p.Pro114Thr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000205 in 1,461,304 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P114A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: KIT NM_000222.3 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 5.05

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, KIT
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.9

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIT	NM_000222.3	c.340C>A	p.Pro114Thr	missense_variant, splice_region_variant	3/21	ENST00000288135.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIT	ENST00000288135.6	c.340C>A	p.Pro114Thr	missense_variant, splice_region_variant	3/21	1	NM_000222.3	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461304 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 726894

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 02, 2022

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; Has not been previously published as pathogenic or benign to our knowledge -

Gastrointestinal stromal tumor Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 16, 2023

This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 114 of the KIT protein (p.Pro114Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with KIT-related conditions. ClinVar contains an entry for this variant (Variation ID: 1037368). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 24, 2022

The p.P114T variant (also known as c.340C>A), located in coding exon 3 of the KIT gene, results from a C to A substitution at nucleotide position 340. The proline at codon 114 is replaced by threonine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Uncertain	2.6	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-5.6	D;D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.025	D;D
Polyphen		0.99	D;D
Vest4		0.77
MutPred		0.58		Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);
MVP		0.81
MPC		1.2
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.49
gMVP		0.94

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

Other links and lift over

dbSNP: rs772836939; hg19: chr4-55564452;