chr15-89321259-G-C
Variant summary
Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM1BP4_Moderate
The NM_002693.3(POLG):c.2600C>G(p.Pro867Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,978 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. P867A) has been classified as Uncertain significance.
Frequency
Consequence
NM_002693.3 missense, splice_region
Scores
Clinical Significance
Conservation
Publications
- progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
- mitochondrial DNA depletion syndrome 4aInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Orphanet, G2P
- sensory ataxic neuropathy, dysarthria, and ophthalmoparesisInheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, G2P
- autosomal dominant progressive external ophthalmoplegiaInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- autosomal recessive progressive external ophthalmoplegiaInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- mitochondrial neurogastrointestinal encephalomyopathyInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- recessive mitochondrial ataxia syndromeInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- spinocerebellar ataxia with epilepsyInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- Leigh syndromeInheritance: AR Classification: LIMITED Submitted by: ClinGen
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ACMG classification
Our verdict: Uncertain_significance. The variant received 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
POLG | NM_002693.3 | c.2600C>G | p.Pro867Arg | missense_variant, splice_region_variant | Exon 17 of 23 | ENST00000268124.11 | NP_002684.1 | |
POLG | NM_001126131.2 | c.2600C>G | p.Pro867Arg | missense_variant, splice_region_variant | Exon 17 of 23 | NP_001119603.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152214Hom.: 0 Cov.: 33 show subpopulations
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461764Hom.: 0 Cov.: 35 AF XY: 0.00000275 AC XY: 2AN XY: 727168 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152214Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74366 show subpopulations
ClinVar
Submissions by phenotype
Progressive sclerosing poliodystrophy Uncertain:1
This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 867 of the POLG protein (p.Pro867Arg). This variant is present in population databases (rs780880601, gnomAD 0.0009%). 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: 528382). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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