4-54272430-A-T
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP2PP3
The NM_006206.6(PDGFRA):c.1274A>T(p.His425Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,822 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H425R) has been classified as Uncertain significance.
Frequency
Consequence
NM_006206.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PDGFRA | NM_006206.6 | c.1274A>T | p.His425Leu | missense_variant | 9/23 | ENST00000257290.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PDGFRA | ENST00000257290.10 | c.1274A>T | p.His425Leu | missense_variant | 9/23 | 1 | NM_006206.6 | P1 | |
PDGFRA | ENST00000509092.5 | n.1092A>T | non_coding_transcript_exon_variant | 8/15 | 1 | ||||
PDGFRA | ENST00000509490.5 | c.1274A>T | p.His425Leu | missense_variant, NMD_transcript_variant | 9/18 | 1 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251360Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135848
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461822Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727228
GnomAD4 genome ? Cov.: 31
ClinVar
Submissions by phenotype
Gastrointestinal stromal tumor Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 20, 2023 | This variant has not been reported in the literature in individuals affected with PDGFRA-related conditions. This sequence change replaces histidine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 425 of the PDGFRA protein (p.His425Leu). This variant is present in population databases (no rsID available, gnomAD 0.003%). ClinVar contains an entry for this variant (Variation ID: 1509076). 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. 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 | Apr 10, 2022 | The p.H425L variant (also known as c.1274A>T), located in coding exon 8 of the PDGFRA gene, results from an A to T substitution at nucleotide position 1274. The histidine at codon 425 is replaced by leucine, an amino acid with similar properties. This amino acid position is conserved. 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at