4-54270644-A-T
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2
The NM_006206.6(PDGFRA):c.1133A>T(p.Lys378Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,604,142 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K378T) has been classified as Likely benign.
Frequency
Consequence
NM_006206.6 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PDGFRA | NM_006206.6 | c.1133A>T | p.Lys378Ile | missense_variant | 8/23 | ENST00000257290.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PDGFRA | ENST00000257290.10 | c.1133A>T | p.Lys378Ile | missense_variant | 8/23 | 1 | NM_006206.6 | P1 | |
PDGFRA | ENST00000509092.5 | n.951A>T | non_coding_transcript_exon_variant | 7/15 | 1 | ||||
PDGFRA | ENST00000509490.5 | c.1133A>T | p.Lys378Ile | missense_variant, NMD_transcript_variant | 8/18 | 1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152220Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251080Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135696
GnomAD4 exome AF: 0.00000964 AC: 14AN: 1451804Hom.: 0 Cov.: 28 AF XY: 0.0000124 AC XY: 9AN XY: 723006
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152338Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4AN XY: 74486
ClinVar
Submissions by phenotype
Polyps, multiple and recurrent inflammatory fibroid, gastrointestinal Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 07, 2024 | - - |
PDGFRA-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 10, 2023 | The PDGFRA c.1133A>T variant is predicted to result in the amino acid substitution p.Lys378Ile. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0085% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-55136811-A-T) and interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/220810/). 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 | Oct 03, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter 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 | Jan 10, 2024 | This sequence change replaces lysine, which is basic and polar, with isoleucine, which is neutral and non-polar, at codon 378 of the PDGFRA protein (p.Lys378Ile). This variant is present in population databases (rs200113704, gnomAD 0.009%). 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: 220810). 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 | Sep 17, 2019 | The p.K378I variant (also known as c.1133A>T), located in coding exon 7 of the PDGFRA gene, results from an A to T substitution at nucleotide position 1133. The lysine at codon 378 is replaced by isoleucine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. 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