rs779961986
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM1BP4_ModerateBP6BS2
The NM_002693.3(POLG):c.1850G>A(p.Arg617His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,613,360 control chromosomes in the GnomAD database, including 2 homozygotes. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R617C) has been classified as Uncertain significance.
Frequency
Consequence
NM_002693.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLG | NM_002693.3 | c.1850G>A | p.Arg617His | missense_variant | 10/23 | ENST00000268124.11 | |
POLGARF | NM_001406557.1 | c.*1122G>A | 3_prime_UTR_variant | 10/23 | |||
POLG | NM_001126131.2 | c.1850G>A | p.Arg617His | missense_variant | 10/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLG | ENST00000268124.11 | c.1850G>A | p.Arg617His | missense_variant | 10/23 | 1 | NM_002693.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152174Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000319 AC: 8AN: 250784Hom.: 1 AF XY: 0.0000369 AC XY: 5AN XY: 135624
GnomAD4 exome AF: 0.0000185 AC: 27AN: 1461186Hom.: 2 Cov.: 33 AF XY: 0.0000193 AC XY: 14AN XY: 726944
GnomAD4 genome AF: 0.0000460 AC: 7AN: 152174Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74336
ClinVar
Submissions by phenotype
not provided Uncertain:3Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | May 02, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 12, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | May 17, 2018 | This variant is associated with the following publications: (PMID: 18546365) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 01, 2019 | - - |
Progressive sclerosing poliodystrophy Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 08, 2022 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 617 of the POLG protein (p.Arg617His). This variant is present in population databases (rs779961986, gnomAD 0.02%). 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: 282075). 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. 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. - |
Benign, 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.1850G>A (NP_002684.1:p.Arg617His) [GRCH38: NC_000015.10:g.89325549C>T] variant in POLG gene is interpretated to be a Benign based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. BS1:The minor allele frequency of this allele is high for Mitochondrial DNA depletion syndrome 4A (Alpers type). BS2:Observation of the variant in controls is inconsistent with penetrance of Mitochondrial DNA depletion syndrome 4A (Alpers type). Based on the evidence criteria codes applied, the variant is suggested to be Benign. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 19, 2020 | The c.1850G>A (p.R617H) alteration is located in exon 10 (coding exon 9) of the POLG gene. This alteration results from a G to A substitution at nucleotide position 1850, causing the arginine (R) at amino acid position 617 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at