rs1307399071
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate
The NM_002693.3(POLG):c.3037G>T(p.Asp1013Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000267 in 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1013N) has been classified as Uncertain significance.
Frequency
Consequence
NM_002693.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLG | NM_002693.3 | c.3037G>T | p.Asp1013Tyr | missense_variant | 19/23 | ENST00000268124.11 | |
POLGARF | NM_001406557.1 | c.*2309G>T | 3_prime_UTR_variant | 19/23 | |||
POLG | NM_001126131.2 | c.3037G>T | p.Asp1013Tyr | missense_variant | 19/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLG | ENST00000268124.11 | c.3037G>T | p.Asp1013Tyr | missense_variant | 19/23 | 1 | NM_002693.3 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251376Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135864
GnomAD4 exome AF: 0.0000267 AC: 39AN: 1461864Hom.: 0 Cov.: 34 AF XY: 0.0000261 AC XY: 19AN XY: 727236
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 11, 2020 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 06, 2017 | A variant of uncertain significance has been identified in the POLG gene. The D1013Y variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The D1013Y variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The D1013Y variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. - |
Progressive sclerosing poliodystrophy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 13, 2021 | This sequence change replaces aspartic acid with tyrosine at codon 1013 of the POLG protein (p.Asp1013Tyr). The aspartic acid residue is moderately conserved and there is a large physicochemical difference between aspartic acid and tyrosine. This variant is not present in population databases (ExAC no frequency). 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: 432740). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). 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