15-89333596-T-TTGCTGCTGCTGCTGCTGCTGCTGCTGCTGC
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The ENST00000268124.11(POLG):c.158_159insGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA(p.Gln46_Gln55dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000066 in 151,604 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. Q53Q) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 30)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
POLG
ENST00000268124.11 inframe_insertion
ENST00000268124.11 inframe_insertion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -2.20
Genes affected
POLG (HGNC:9179): (DNA polymerase gamma, catalytic subunit) Mitochondrial DNA polymerase is heterotrimeric, consisting of a homodimer of accessory subunits plus a catalytic subunit. The protein encoded by this gene is the catalytic subunit of mitochondrial DNA polymerase. The encoded protein contains a polyglutamine tract near its N-terminus that may be polymorphic. Defects in this gene are a cause of progressive external ophthalmoplegia with mitochondrial DNA deletions 1 (PEOA1), sensory ataxic neuropathy dysarthria and ophthalmoparesis (SANDO), Alpers-Huttenlocher syndrome (AHS), and mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE). Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]
POLGARF (HGNC:56246): (POLG alternative reading frame) This gene uses the same transcript as the POLG gene but has a CUG start codon and an alternate reading frame that makes a 260 aa protein. This protein is distinct from POLG isoforms and may interact with P32 (also known as C1QBP), a mitochondrial matrix protein thought to be involved in the expression of mitochondrial genome-encoded proteins. POLGARF protein may bind P32 and sequester it in the nucleolus. Interestingly, some disease-causing mutations thought to be in POLG may instead be associated with POLGARF. [provided by RefSeq, May 2022]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| POLG | NM_002693.3 | c.158_159insGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA | p.Gln46_Gln55dup | inframe_insertion | 2/23 | ENST00000268124.11 | NP_002684.1 | |
| POLGARF | NM_001406557.1 | c.213_214insGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA | p.Ala62_Ala71dup | inframe_insertion | 2/23 | NP_001393486.1 | ||
| POLG | NM_001126131.2 | c.158_159insGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA | p.Gln46_Gln55dup | inframe_insertion | 2/23 | NP_001119603.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| POLG | ENST00000268124.11 | c.158_159insGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA | p.Gln46_Gln55dup | inframe_insertion | 2/23 | 1 | NM_002693.3 | ENSP00000268124 | P1 | |
| POLGARF | ENST00000706918.1 | c.213_214insGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA | p.Ala62_Ala71dup | inframe_insertion | 1/2 | ENSP00000516626 | P1 |
Frequencies
GnomAD3 genomes 0.00000660 AC: 1AN: 151604Hom.: 0 Cov.: 30
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.91e-7 AC: 1AN: 1446396Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 719198
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GnomAD4 genome 0.00000660 AC: 1AN: 151604Hom.: 0 Cov.: 30 AF XY: 0.0000135 AC XY: 1AN XY: 74046
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Progressive sclerosing poliodystrophy Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 08, 2023 | This variant, c.129_158dup, results in the insertion of 10 amino acid(s) of the POLG protein (p.Gln46_Gln55dup), but otherwise preserves the integrity of the reading frame. 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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at