rs764195223
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate
The NM_002693.3(POLG):c.3040A>G(p.Arg1014Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,614,050 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. R1014K) has been classified as Uncertain significance.
Frequency
Consequence
NM_002693.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLG | NM_002693.3 | c.3040A>G | p.Arg1014Gly | missense_variant | 19/23 | ENST00000268124.11 | |
POLGARF | NM_001406557.1 | c.*2312A>G | 3_prime_UTR_variant | 19/23 | |||
POLG | NM_001126131.2 | c.3040A>G | p.Arg1014Gly | missense_variant | 19/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLG | ENST00000268124.11 | c.3040A>G | p.Arg1014Gly | missense_variant | 19/23 | 1 | NM_002693.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152190Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251362Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135860
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461860Hom.: 0 Cov.: 34 AF XY: 0.00000413 AC XY: 3AN XY: 727228
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152190Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74338
ClinVar
Submissions by phenotype
Progressive sclerosing poliodystrophy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 04, 2024 | This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 1014 of the POLG protein (p.Arg1014Gly). This variant is present in population databases (rs764195223, gnomAD 0.01%). 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: 430472). 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 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine | Oct 01, 2018 | The NM_002693.2:c.3040A>G (NP_002684.1:p.Arg1014Gly) [GRCH38: NC_000015.10:g.89319292T>C] variant in POLG gene is interpretated to be a Uncertain Significance based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. PM2:This variant is absent in key population databases. PP3:Computational evidence/predictors indicate the variant has deleterious effect on POLG structure, function, or protein-protein interaction. Based on the evidence criteria codes applied, the variant is suggested to be Uncertain Significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 22, 2017 | The R1014G variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R1014G variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R1014G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at