15-89319234-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP3BP6
The NM_002693.3(POLG):c.3098C>T(p.Ala1033Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00022 in 1,614,122 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/23 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. A1033K) has been classified as Uncertain significance.
Frequency
Consequence
NM_002693.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLG | NM_002693.3 | c.3098C>T | p.Ala1033Val | missense_variant | 19/23 | ENST00000268124.11 | |
POLGARF | NM_001406557.1 | c.*2370C>T | 3_prime_UTR_variant | 19/23 | |||
POLG | NM_001126131.2 | c.3098C>T | p.Ala1033Val | missense_variant | 19/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLG | ENST00000268124.11 | c.3098C>T | p.Ala1033Val | missense_variant | 19/23 | 1 | NM_002693.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000342 AC: 52AN: 152118Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.000255 AC: 64AN: 251460Hom.: 0 AF XY: 0.000243 AC XY: 33AN XY: 135906
GnomAD4 exome AF: 0.000207 AC: 303AN: 1461886Hom.: 0 Cov.: 34 AF XY: 0.000202 AC XY: 147AN XY: 727244
GnomAD4 genome AF: 0.000342 AC: 52AN: 152236Hom.: 1 Cov.: 32 AF XY: 0.000443 AC XY: 33AN XY: 74442
ClinVar
Submissions by phenotype
not provided Uncertain:4Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 16, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 26, 2020 | This variant is associated with the following publications: (PMID: 21880868, 30290626) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 21, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Apr 01, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jul 31, 2020 | - - |
Progressive sclerosing poliodystrophy Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
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.3098C>T (NP_002684.1:p.Ala1033Val) [GRCH38: NC_000015.10:g.89319234G>A] 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. BS2:Observation of the variant in controls is inconsistent with penetrance of Mitochondrial DNA depletion syndrome 4A (Alpers type). BP4:Computational evidence/predictors indicate no impact on the POLG structure, function, or protein-protein interaction. 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. - |
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 09, 2020 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
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
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
POLG-Related Spectrum Disorders Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at