rs758137485
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2
The NM_006206.6(PDGFRA):c.1492G>A(p.Ala498Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000929 in 1,613,922 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A498V) has been classified as Uncertain significance.
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000068 ( 0 hom. )
Consequence
PDGFRA
NM_006206.6 missense
NM_006206.6 missense
Scores
1
4
14
Clinical Significance
Conservation
PhyloP100: 5.67
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 Likely_benign. Variant got -3 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, PDGFRA
BS2
?
High AC in GnomAd4 at 5 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PDGFRA | NM_006206.6 | c.1492G>A | p.Ala498Thr | missense_variant | 10/23 | ENST00000257290.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PDGFRA | ENST00000257290.10 | c.1492G>A | p.Ala498Thr | missense_variant | 10/23 | 1 | NM_006206.6 | P1 | |
PDGFRA | ENST00000509092.5 | n.1310G>A | non_coding_transcript_exon_variant | 9/15 | 1 | ||||
PDGFRA | ENST00000509490.5 | c.1492G>A | p.Ala498Thr | missense_variant, NMD_transcript_variant | 10/18 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152110Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000199 AC: 5AN: 250918Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135636
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GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461812Hom.: 0 Cov.: 33 AF XY: 0.00000825 AC XY: 6AN XY: 727208
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
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 | Nov 21, 2023 | - - |
Gastrointestinal stromal tumor Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 498 of the PDGFRA protein (p.Ala498Thr). This variant is present in population databases (rs758137485, gnomAD 0.008%). 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: 407407). 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 | Aug 24, 2022 | The p.A498T variant (also known as c.1492G>A), located in coding exon 9 of the PDGFRA gene, results from a G to A substitution at nucleotide position 1492. The alanine at codon 498 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Benign
T
MetaRNN
Uncertain
D
MetaSVM
Benign
T
MutationAssessor
Benign
L
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Benign
Sift
Benign
T
Sift4G
Benign
T
Polyphen
D
Vest4
MutPred
Gain of phosphorylation at A498 (P = 0.0252);
MVP
MPC
ClinPred
T
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