chr15-89326927-G-C
Variant summary
Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong
The NM_002693.3(POLG):c.1570C>G(p.Pro524Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000031 in 1,614,094 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P524P) has been classified as Likely benign.
Frequency
Consequence
NM_002693.3 missense
Scores
Clinical Significance
Conservation
Publications
Genome browser will be placed here
ACMG classification
Our verdict: Likely_benign. The variant received -4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152140Hom.: 0 Cov.: 33 show subpopulations
GnomAD2 exomes AF: 0.0000358 AC: 9AN: 251228 AF XY: 0.0000515 show subpopulations
GnomAD4 exome AF: 0.0000328 AC: 48AN: 1461836Hom.: 0 Cov.: 34 AF XY: 0.0000385 AC XY: 28AN XY: 727222 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152258Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74424 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not provided Uncertain:3
- -
- -
p.Pro524Ala (CCC>GCC): c.1570 C>G in exon 8 of the POLG gene (NM_002693.2). The P524A variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position that is not conserved across species, and Alanine has been seen at this position in evolution. In silico analysis predicts this variant likely does not alter the protein structure/function. However, the P524A variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in EPILEPSY panel(s). -
Progressive sclerosing poliodystrophy;C1834846:Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1;C1843851:Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis;C3150914:Mitochondrial DNA depletion syndrome 4b;C4225153:Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1;C4551995:Mitochondrial DNA depletion syndrome 1 Uncertain:1
- -
Progressive sclerosing poliodystrophy Uncertain:1
This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 524 of the POLG protein (p.Pro524Ala). This variant is present in population databases (rs577476988, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with POLG-related conditions. ClinVar contains an entry for this variant (Variation ID: 206631). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt POLG protein function with a negative predictive value of 95%. 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at