rs1057519702

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PM5PP2

The NM_000222.3(KIT):​c.1510T>A​(p.Phe504Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F504L) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

KIT
NM_000222.3 missense

Scores

3
11
5

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.11
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr4-54726020-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 375904.Status of the report is no_assertion_criteria_provided, 0 stars.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KIT. . Gene score misZ 2.5806 (greater than the threshold 3.09). Trascript score misZ 4.1549 (greater than threshold 3.09). GenCC has associacion of gene with piebaldism, gastrointestinal stromal tumor, mastocytosis, cutaneous mastocytosis.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
KITNM_000222.3 linkuse as main transcriptc.1510T>A p.Phe504Ile missense_variant 9/21 ENST00000288135.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
KITENST00000288135.6 linkuse as main transcriptc.1510T>A p.Phe504Ile missense_variant 9/211 NM_000222.3 P4P10721-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.54
BayesDel_addAF
Uncertain
0.14
D
BayesDel_noAF
Uncertain
-0.030
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.46
.;T
Eigen
Pathogenic
0.81
Eigen_PC
Pathogenic
0.79
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.92
D;D
M_CAP
Uncertain
0.12
D
MetaRNN
Uncertain
0.67
D;D
MetaSVM
Uncertain
0.39
D
MutationAssessor
Uncertain
2.8
M;M
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.65
T
PROVEAN
Benign
-2.0
N;N
REVEL
Benign
0.29
Sift
Benign
0.32
T;D
Sift4G
Benign
0.17
T;T
Polyphen
0.99
D;D
Vest4
0.68
MutPred
0.44
Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);
MVP
0.77
MPC
1.6
ClinPred
0.98
D
GERP RS
6.0
Varity_R
0.59
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-55592186; API