rs145019788
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2
The NM_006206.6(PDGFRA):c.2965A>C(p.Ile989Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_006206.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PDGFRA | ENST00000257290.10 | c.2965A>C | p.Ile989Leu | missense_variant | Exon 22 of 23 | 1 | NM_006206.6 | ENSP00000257290.5 | ||
ENSG00000282278 | ENST00000507166.5 | c.2245A>C | p.Ile749Leu | missense_variant | Exon 23 of 24 | 2 | ENSP00000423325.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152228Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251356Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135840
GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461428Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6AN XY: 727048
GnomAD4 genome AF: 0.00000656 AC: 1AN: 152346Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74496
ClinVar
Submissions by phenotype
Gastrointestinal stromal tumor Uncertain:1
This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 989 of the PDGFRA protein (p.Ile989Leu). This variant is present in population databases (rs145019788, gnomAD 0.04%). 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: 528553). 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 Benign:1
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at