rs753407311
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1BP4
The NM_002693.3(POLG):āc.744G>Cā(p.Glu248Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,613,686 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Consequence
NM_002693.3 missense
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.744G>C | p.Glu248Asp | missense_variant | 3/23 | ENST00000268124.11 | |
POLGARF | NM_001406557.1 | c.*16G>C | 3_prime_UTR_variant | 3/23 | |||
POLG | NM_001126131.2 | c.744G>C | p.Glu248Asp | missense_variant | 3/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLG | ENST00000268124.11 | c.744G>C | p.Glu248Asp | missense_variant | 3/23 | 1 | NM_002693.3 | P1 | |
POLGARF | ENST00000706918.1 | downstream_gene_variant | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000723 AC: 11AN: 152234Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251140Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135846
GnomAD4 exome AF: 0.0000137 AC: 20AN: 1461452Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10AN XY: 727040
GnomAD4 genome ? AF: 0.0000723 AC: 11AN: 152234Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6AN XY: 74372
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 10, 2020 | The c.744G>C (p.E248D) alteration is located in exon 3 (coding exon 2) of the POLG gene. This alteration results from a G to C substitution at nucleotide position 744, causing the glutamic acid (E) at amino acid position 248 to be replaced by an aspartic acid (D). Based on data from the Genome Aggregation Database (gnomAD) database, the POLG c.744G>C alteration was observed in <0.01% (9/282540) of total alleles studied, with a frequency of 0.04% (9/24944) in the African subpopulation. This amino acid position is well conserved in available vertebrate species. The p.E248D alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 22, 2021 | In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Progressive sclerosing poliodystrophy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 17, 2022 | This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 248 of the POLG protein (p.Glu248Asp). This variant is present in population databases (rs753407311, gnomAD 0.04%). 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: 431892). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at