rs78347903
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1BP4_Moderate
The NM_002693.3(POLG):c.2218A>G(p.Asn740Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000044 in 1,614,002 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. N740N) has been classified as Likely benign.
Frequency
Consequence
NM_002693.3 missense
Scores
Clinical Significance
Conservation
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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.2218A>G | p.Asn740Asp | missense_variant | 13/23 | ENST00000268124.11 | |
POLGARF | NM_001406557.1 | c.*1490A>G | 3_prime_UTR_variant | 13/23 | |||
POLG | NM_001126131.2 | c.2218A>G | p.Asn740Asp | missense_variant | 13/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLG | ENST00000268124.11 | c.2218A>G | p.Asn740Asp | missense_variant | 13/23 | 1 | NM_002693.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152092Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251386Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135882
GnomAD4 exome AF: 0.0000431 AC: 63AN: 1461792Hom.: 0 Cov.: 31 AF XY: 0.0000426 AC XY: 31AN XY: 727216
GnomAD4 genome ? AF: 0.0000526 AC: 8AN: 152210Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74418
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 25, 2013 | p.Asn740Asp (AAC>GAC): c.2218 A>G in exon 13 of the POLG gene (NM_002693.2). The Asn740Asp missense change in the POLG gene has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. This variant is a non-conservative amino acid substitution of an uncharged Asparagine residue with a negatively charged Aspartic acid residue. While this variant alters a position that is not highly conserved across species and Asparagine is observed at this position in other species, several other missense mutations associated with POLG-related disorders are reported in this region of the protein (N736S, G737R, G746S, W748S). In silico analysis is inconsistent with regard to the effect this variant may have on the protein structure/function. Therefore, based on the currently available information, it is unclear whether Asn740Asp is a disease-causing mutation or a rare benign variant. The variant is found in INFANT-EPI panel(s). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 02, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jan 10, 2018 | - - |
POLG-Related Spectrum Disorders Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 12, 2017 | The p.N740D variant (also known as c.2218A>G), located in coding exon 12 of the POLG gene, results from an A to G substitution at nucleotide position 2218. The asparagine at codon 740 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species, and aspartic acid is the reference amino acid in other 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. - |
Vascular dementia Uncertain:1
Uncertain significance, no assertion criteria provided | research | Myllykangas group, University of Helsinki | Oct 01, 2021 | - - |
Progressive sclerosing poliodystrophy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 11, 2023 | This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 740 of the POLG protein (p.Asn740Asp). This variant is present in population databases (rs78347903, gnomAD 0.005%). This missense change has been observed in individual(s) with vascular dementia (PMID: 35307828). ClinVar contains an entry for this variant (Variation ID: 206519). 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. - |
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 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | New York Genome Center | Jun 16, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at