rs775373016
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2
The NM_006206.6(PDGFRA):āc.1347A>Gā(p.Ile449Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000353 in 1,614,058 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 Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I449T) has been classified as Uncertain significance.
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.1347A>G | p.Ile449Met | missense_variant | 9/23 | ENST00000257290.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PDGFRA | ENST00000257290.10 | c.1347A>G | p.Ile449Met | missense_variant | 9/23 | 1 | NM_006206.6 | P1 | |
PDGFRA | ENST00000509092.5 | n.1165A>G | non_coding_transcript_exon_variant | 8/15 | 1 | ||||
PDGFRA | ENST00000509490.5 | c.1347A>G | p.Ile449Met | missense_variant, NMD_transcript_variant | 9/18 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152200Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000478 AC: 12AN: 251126Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135728
GnomAD4 exome AF: 0.0000342 AC: 50AN: 1461740Hom.: 0 Cov.: 32 AF XY: 0.0000385 AC XY: 28AN XY: 727186
GnomAD4 genome ? AF: 0.0000460 AC: 7AN: 152318Hom.: 0 Cov.: 31 AF XY: 0.0000806 AC XY: 6AN XY: 74478
ClinVar
Submissions by phenotype
Gastrointestinal stromal tumor Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 449 of the PDGFRA protein (p.Ile449Met). This variant is present in population databases (rs775373016, 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: 407390). 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 | Jan 13, 2020 | The p.I449M variant (also known as c.1347A>G), located in coding exon 8 of the PDGFRA gene, results from an A to G substitution at nucleotide position 1347. The isoleucine at codon 449 is replaced by methionine, an amino acid with highly similar 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