15-89318572-G-A
Variant summary
Our verdict is Uncertain significance. Variant got -1 ACMG points: 0P and 1B. BP7
This summary comes from the ClinGen Evidence Repository: The c.3451C>T (p.L1151L) variant in POLG is present in population databases ExAC at 0.11% frequency and not observed in homozygotes (no criteria is met). There is limited computational predictions and the tool Revel unavailable given limited data. This variant is a coding synonymous change (BP7). In summary, there is not sufficient evidence to characterize this variant as pathogenic or benign, therefore it is characterized as a variant of uncertain significance for primary mitochondrial disease inherited in a autosomal recessive manner.ntDNA Mitochondrial ACMG-AMP Criteria for POLG applied: BP7 LINK:https://erepo.genome.network/evrepo/ui/classification/CA7724139/MONDO:0044970/014
Frequency
Consequence
NM_002693.3 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLG | NM_002693.3 | c.3451C>T | p.Leu1151= | synonymous_variant | 21/23 | ENST00000268124.11 | |
POLGARF | NM_001406557.1 | c.*2723C>T | 3_prime_UTR_variant | 21/23 | |||
POLG | NM_001126131.2 | c.3451C>T | p.Leu1151= | synonymous_variant | 21/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLG | ENST00000268124.11 | c.3451C>T | p.Leu1151= | synonymous_variant | 21/23 | 1 | NM_002693.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152228Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000517 AC: 13AN: 251356Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135874
GnomAD4 exome AF: 0.0000506 AC: 74AN: 1461530Hom.: 0 Cov.: 32 AF XY: 0.0000509 AC XY: 37AN XY: 727068
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152228Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74368
ClinVar
Submissions by phenotype
Progressive sclerosing poliodystrophy Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 24, 2023 | - - |
Likely 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.3451C>T (NP_002684.1:p.Leu1151=) [GRCH38: NC_000015.10:g.89318572G>A] variant in POLG gene is interpretated to be a Likely 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). BP4:Computational evidence/predictors indicate no impact on the POLG structure, function, or protein-protein interaction. BP7:The variant is silent with non predicted splice impact. Based on the evidence criteria codes applied, the variant is suggested to be Likely Benign. - |
Mitochondrial disease Uncertain:1
Uncertain significance, reviewed by expert panel | curation | ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen | May 06, 2021 | The c.3451C>T (p.L1151L) variant in POLG is present in population databases ExAC at 0.11% frequency and not observed in homozygotes (no criteria is met). There is limited computational predictions and the tool Revel unavailable given limited data. This variant is a coding synonymous change (BP7). In summary, there is not sufficient evidence to characterize this variant as pathogenic or benign, therefore it is characterized as a variant of uncertain significance for primary mitochondrial disease inherited in a autosomal recessive manner. ntDNA Mitochondrial ACMG-AMP Criteria for POLG applied: BP7 - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 29, 2015 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
POLG-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 08, 2019 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at