rs908875872
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1BP4_Strong
The NM_002693.3(POLG):c.1894G>A(p.Ala632Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000373 in 1,610,406 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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. A632A) has been classified as Likely benign.
Frequency
Consequence
NM_002693.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLG | NM_002693.3 | c.1894G>A | p.Ala632Thr | missense_variant | 10/23 | ENST00000268124.11 | |
POLGARF | NM_001406557.1 | c.*1166G>A | 3_prime_UTR_variant | 10/23 | |||
POLG | NM_001126131.2 | c.1894G>A | p.Ala632Thr | missense_variant | 10/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLG | ENST00000268124.11 | c.1894G>A | p.Ala632Thr | missense_variant | 10/23 | 1 | NM_002693.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152148Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000343 AC: 5AN: 1458258Hom.: 0 Cov.: 33 AF XY: 0.00000276 AC XY: 2AN XY: 725602
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152148Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74308
ClinVar
Submissions by phenotype
Progressive sclerosing poliodystrophy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 26, 2022 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 632 of the POLG protein (p.Ala632Thr). This variant is not present in population databases (gnomAD 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: 597713). 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. - |
Uncertain significance, 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.1894G>A (NP_002684.1:p.Ala632Thr) [GRCH38: NC_000015.10:g.89325505C>T] variant in POLG gene is interpretated to be a Uncertain Significance based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. 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 Uncertain Significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 03, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at