rs1057519812

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP2PP3_StrongPP5

The NM_006206.6(PDGFRA):​c.1973T>C​(p.Val658Ala) 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 Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V658L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Consequence

PDGFRA
NM_006206.6 missense

Scores

9
8
2

Clinical Significance

Likely pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.95
Variant links:
Genes affected
PDGFRA (HGNC:8803): (platelet derived growth factor receptor alpha) This gene encodes a cell surface tyrosine kinase receptor for members of the platelet-derived growth factor family. These growth factors are mitogens for cells of mesenchymal origin. The identity of the growth factor bound to a receptor monomer determines whether the functional receptor is a homodimer or a heterodimer, composed of both platelet-derived growth factor receptor alpha and beta polypeptides. Studies suggest that this gene plays a role in organ development, wound healing, and tumor progression. Mutations in this gene have been associated with idiopathic hypereosinophilic syndrome, somatic and familial gastrointestinal stromal tumors, and a variety of other cancers. [provided by RefSeq, Mar 2012]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 uncertain in NM_006206.6
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PDGFRA. . Gene score misZ 1.9401 (greater than the threshold 3.09). Trascript score misZ 3.4078 (greater than threshold 3.09). GenCC has associacion of gene with congenital heart disease, polyps, multiple and recurrent inflammatory fibroid, gastrointestinal, gastrointestinal stromal tumor, isolated cleft palate.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.959
PP5
Variant 4-54277977-T-C is Pathogenic according to our data. Variant chr4-54277977-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376182.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PDGFRANM_006206.6 linkuse as main transcriptc.1973T>C p.Val658Ala missense_variant 14/23 ENST00000257290.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PDGFRAENST00000257290.10 linkuse as main transcriptc.1973T>C p.Val658Ala missense_variant 14/231 NM_006206.6 P1P16234-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Melanoma Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)Dec 26, 2014- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.44
D
BayesDel_noAF
Pathogenic
0.39
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.74
.;D
Eigen
Pathogenic
0.81
Eigen_PC
Pathogenic
0.79
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Benign
0.78
T;D
M_CAP
Uncertain
0.18
D
MetaRNN
Pathogenic
0.96
D;D
MetaSVM
Pathogenic
0.92
D
MutationAssessor
Uncertain
2.1
.;M
MutationTaster
Benign
0.73
D;D
PrimateAI
Pathogenic
0.94
D
PROVEAN
Uncertain
-2.7
D;D
REVEL
Pathogenic
0.84
Sift
Uncertain
0.0040
D;D
Sift4G
Uncertain
0.0030
D;D
Polyphen
1.0
.;D
Vest4
0.87
MutPred
0.86
.;Loss of stability (P = 0.0265);
MVP
0.91
MPC
1.2
ClinPred
0.97
D
GERP RS
5.8
Varity_R
0.67
gMVP
0.89

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.

Other links and lift over

dbSNP: rs1057519812; hg19: chr4-55144144; API