rs1411219168
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_002693.3(POLG):c.1672C>G(p.Leu558Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,992 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. L558L) 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.1672C>G | p.Leu558Val | missense_variant | 9/23 | ENST00000268124.11 | |
POLGARF | NM_001406557.1 | c.*944C>G | 3_prime_UTR_variant | 9/23 | |||
POLG | NM_001126131.2 | c.1672C>G | p.Leu558Val | missense_variant | 9/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLG | ENST00000268124.11 | c.1672C>G | p.Leu558Val | missense_variant | 9/23 | 1 | NM_002693.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152182Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251312Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135870
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461810Hom.: 0 Cov.: 33 AF XY: 0.0000110 AC XY: 8AN XY: 727222
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152182Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74342
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 21, 2022 | Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function - |
Progressive sclerosing poliodystrophy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 14, 2022 | This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 558 of the POLG protein (p.Leu558Val). This variant is present in population databases (no rsID available, gnomAD 0.009%). 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: 458691). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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