chr4-54274855-A-T
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2
The NM_006206.6(PDGFRA):c.1668A>T(p.Glu556Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,613,982 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000023 ( 0 hom. )
Consequence
PDGFRA
NM_006206.6 missense
NM_006206.6 missense
Scores
6
10
3
Clinical Significance
Conservation
PhyloP100: 1.19
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 GnomAdExome4 at 33 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PDGFRA | NM_006206.6 | c.1668A>T | p.Glu556Asp | missense_variant | 12/23 | ENST00000257290.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PDGFRA | ENST00000257290.10 | c.1668A>T | p.Glu556Asp | missense_variant | 12/23 | 1 | NM_006206.6 | P1 | |
PDGFRA | ENST00000509092.5 | n.1486A>T | non_coding_transcript_exon_variant | 11/15 | 1 | ||||
PDGFRA | ENST00000509490.5 | c.1668A>T | p.Glu556Asp | missense_variant, NMD_transcript_variant | 12/18 | 1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152130Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.0000226 AC: 33AN: 1461852Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12AN XY: 727232
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152130Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74328
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 17, 2023 | 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 | Aug 17, 2023 | This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 556 of the PDGFRA protein (p.Glu556Asp). This variant is not present in population databases (gnomAD no frequency). 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: 528502). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PDGFRA protein function. 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 | Jul 09, 2023 | The p.E556D variant (also known as c.1668A>T), located in coding exon 11 of the PDGFRA gene, results from an A to T substitution at nucleotide position 1668. The glutamic acid at codon 556 is replaced by aspartic acid, an amino acid with highly 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
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
T
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Benign
D
MetaRNN
Uncertain
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
Gain of MoRF binding (P = 0.0999);
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