rs1294452177
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP2PP3
The NM_006206.6(PDGFRA):āc.1580T>Cā(p.Val527Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,802 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 Uncertain significance (ā ā ).
Frequency
Genomes: š 0.000013 ( 0 hom., cov: 32)
Exomes š: 0.0000027 ( 0 hom. )
Consequence
PDGFRA
NM_006206.6 missense
NM_006206.6 missense
Scores
5
10
4
Clinical Significance
Conservation
PhyloP100: 7.60
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 Uncertain_significance. Variant got 2 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, PDGFRA
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.775
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PDGFRA | NM_006206.6 | c.1580T>C | p.Val527Ala | missense_variant | 11/23 | ENST00000257290.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PDGFRA | ENST00000257290.10 | c.1580T>C | p.Val527Ala | missense_variant | 11/23 | 1 | NM_006206.6 | P1 | |
PDGFRA | ENST00000509092.5 | n.1398T>C | non_coding_transcript_exon_variant | 10/15 | 1 | ||||
PDGFRA | ENST00000509490.5 | c.1580T>C | p.Val527Ala | missense_variant, NMD_transcript_variant | 11/18 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152208Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251182Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135756
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461594Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727132
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152208Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74374
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Polyps, multiple and recurrent inflammatory fibroid, gastrointestinal Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 07, 2024 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2023 | - - |
Gastrointestinal stromal tumor Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 05, 2023 | This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 527 of the PDGFRA protein (p.Val527Ala). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with PDGFRA-related conditions. ClinVar contains an entry for this variant (Variation ID: 528559). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PDGFRA protein function with a negative predictive value of 80%. 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 | Oct 13, 2023 | The p.V527A variant (also known as c.1580T>C), located in coding exon 10 of the PDGFRA gene, results from a T to C substitution at nucleotide position 1580. The valine at codon 527 is replaced by alanine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Benign
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Uncertain
T
Polyphen
D
Vest4
MutPred
Gain of disorder (P = 0.1738);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at