rs115109291
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4_StrongBP6
The NM_002693.3(POLG):āc.408C>Gā(p.Asp136Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000149 in 1,568,212 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. D136Y) 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 -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLG | NM_002693.3 | c.408C>G | p.Asp136Glu | missense_variant | 2/23 | ENST00000268124.11 | |
POLGARF | NM_001406557.1 | c.463C>G | p.Pro155Ala | missense_variant | 2/23 | ||
POLG | NM_001126131.2 | c.408C>G | p.Asp136Glu | missense_variant | 2/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLG | ENST00000268124.11 | c.408C>G | p.Asp136Glu | missense_variant | 2/23 | 1 | NM_002693.3 | P1 | |
POLGARF | ENST00000706918.1 | c.463C>G | p.Pro155Ala | missense_variant | 1/2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000755 AC: 115AN: 152252Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.000227 AC: 40AN: 176174Hom.: 0 AF XY: 0.000104 AC XY: 10AN XY: 96018
GnomAD4 exome AF: 0.0000833 AC: 118AN: 1415842Hom.: 0 Cov.: 32 AF XY: 0.0000699 AC XY: 49AN XY: 701130
GnomAD4 genome ? AF: 0.000761 AC: 116AN: 152370Hom.: 0 Cov.: 34 AF XY: 0.000751 AC XY: 56AN XY: 74520
ClinVar
Submissions by phenotype
not provided Uncertain:4Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 26, 2021 | Observed as heterozygous in two siblings with epilepsy and was considered by the authors to be a variant of unknown clinical significance (Blok et al., 2009).; This variant is associated with the following publications: (PMID: 24508722, 21880868, 19578034) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | May 13, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Apr 27, 2023 | BP4 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Apr 17, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 29, 2018 | - - |
Progressive sclerosing poliodystrophy Benign:2
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.408C>G (NP_002684.1:p.Asp136Glu) [GRCH38: NC_000015.10:g.89333347G>C] 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. Based on the evidence criteria codes applied, the variant is suggested to be Likely Benign. - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 03, 2018 | The p.D136E variant (also known as c.408C>G), located in coding exon 1 of the POLG gene, results from a C to G substitution at nucleotide position 408. The aspartic acid at codon 136 is replaced by glutamic acid, an amino acid with highly similar properties. This alteration was detected in two brothers with epilepsy who had p.Q45R on the other chromosome; the variant was not found in 100 control individuals (Blok MJ et al. J. Med. Genet., 2009 Nov;46:776-85). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
POLG-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 27, 2022 | 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