rs2307442
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_002693.3(POLG):c.3424C>T(p.Arg1142Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000316 in 1,614,112 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R1142Q) has been classified as Likely benign.
Frequency
Consequence
NM_002693.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000788 AC: 12AN: 152188Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000438 AC: 11AN: 251404Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135884
GnomAD4 exome AF: 0.0000267 AC: 39AN: 1461806Hom.: 0 Cov.: 32 AF XY: 0.0000248 AC XY: 18AN XY: 727196
GnomAD4 genome AF: 0.0000788 AC: 12AN: 152306Hom.: 0 Cov.: 32 AF XY: 0.0000671 AC XY: 5AN XY: 74476
ClinVar
Submissions by phenotype
POLG-Related Spectrum Disorders Uncertain:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
POLG-related disorder Uncertain:1
The POLG c.3424C>T variant is predicted to result in the amino acid substitution p.Arg1142Trp. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.044% of alleles in individuals of African descent in gnomAD. 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
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Progressive sclerosing poliodystrophy Uncertain:1
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1142 of the POLG protein (p.Arg1142Trp). This variant is present in population databases (rs2307442, gnomAD 0.05%). 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: 21311). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on POLG 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at