rs375047532
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS2
The NM_006206.6(PDGFRA):āc.1388C>Gā(p.Thr463Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000172 in 1,614,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T463I) has been classified as Uncertain significance.
Frequency
Consequence
NM_006206.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PDGFRA | NM_006206.6 | c.1388C>G | p.Thr463Ser | missense_variant | 10/23 | ENST00000257290.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PDGFRA | ENST00000257290.10 | c.1388C>G | p.Thr463Ser | missense_variant | 10/23 | 1 | NM_006206.6 | P1 | |
PDGFRA | ENST00000509092.5 | n.1206C>G | non_coding_transcript_exon_variant | 9/15 | 1 | ||||
PDGFRA | ENST00000509490.5 | c.1388C>G | p.Thr463Ser | missense_variant, NMD_transcript_variant | 10/18 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000723 AC: 11AN: 152164Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000191 AC: 48AN: 251150Hom.: 0 AF XY: 0.000236 AC XY: 32AN XY: 135750
GnomAD4 exome AF: 0.000182 AC: 266AN: 1461780Hom.: 0 Cov.: 32 AF XY: 0.000197 AC XY: 143AN XY: 727194
GnomAD4 genome ? AF: 0.0000722 AC: 11AN: 152282Hom.: 0 Cov.: 31 AF XY: 0.0000940 AC XY: 7AN XY: 74450
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Dec 23, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 03, 2023 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Polyps, multiple and recurrent inflammatory fibroid, gastrointestinal Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Jul 25, 2023 | The PDGFRA c.1388C>G (p.Thr463Ser) missense change has a maximum subpopulation frequency of 0.068% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with PDGFRA-related conditions. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. - |
PDGFRA-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 27, 2023 | The PDGFRA c.1388C>G variant is predicted to result in the amino acid substitution p.Thr463Ser. This variant was reported in an individual with sarcoma (Jouenne et al. 2017. PubMed ID: 28592523). This variant is reported in 0.069% of alleles in individuals of South Asian descent in gnomAD and has conflicting interpretations of pathogenicity of likely benign and uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/240305/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 30, 2023 | In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals from one family with melanoma and sarcoma, some of whom also carried a variant in CDKN2A (Jouenne et al., 2017); This variant is associated with the following publications: (PMID: 28592523) - |
Gastrointestinal stromal tumor Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 21, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at