chr15-89333627-T-TGCC
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Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6
The NM_002693.3(POLG):c.125_127dupGGC(p.Arg42dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000267 in 1,581,520 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00038 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00025 ( 1 hom. )
Consequence
POLG
NM_002693.3 conservative_inframe_insertion
NM_002693.3 conservative_inframe_insertion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.749
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 Likely_benign. Variant got -1 ACMG points.
BP6
Variant 15-89333627-T-TGCC is Benign according to our data. Variant chr15-89333627-T-TGCC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 419072.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=4}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
POLG | NM_002693.3 | c.125_127dupGGC | p.Arg42dup | conservative_inframe_insertion | Exon 2 of 23 | ENST00000268124.11 | NP_002684.1 | |
POLG | NM_001126131.2 | c.125_127dupGGC | p.Arg42dup | conservative_inframe_insertion | Exon 2 of 23 | NP_001119603.1 | ||
POLGARF | NM_001430120.1 | c.180_182dupGGC | p.Ala61dup | disruptive_inframe_insertion | Exon 1 of 2 | NP_001417049.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
POLG | ENST00000268124.11 | c.125_127dupGGC | p.Arg42dup | conservative_inframe_insertion | Exon 2 of 23 | 1 | NM_002693.3 | ENSP00000268124.5 | ||
POLGARF | ENST00000706918.1 | c.180_182dupGGC | p.Ala61dup | disruptive_inframe_insertion | Exon 1 of 2 | ENSP00000516626.1 |
Frequencies
GnomAD3 genomes AF: 0.000382 AC: 58AN: 151704Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000139 AC: 28AN: 202064Hom.: 0 AF XY: 0.000125 AC XY: 14AN XY: 111630
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GnomAD4 exome AF: 0.000255 AC: 364AN: 1429704Hom.: 1 Cov.: 32 AF XY: 0.000254 AC XY: 180AN XY: 709874
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GnomAD4 genome AF: 0.000382 AC: 58AN: 151816Hom.: 0 Cov.: 33 AF XY: 0.000364 AC XY: 27AN XY: 74206
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:4
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:4Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Dec 14, 2015 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Aug 21, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 10, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | May 01, 2024 | PM4 - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jul 22, 2022 | See Variant Classification Assertion Criteria. - |
POLG-related disorder Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 08, 2024 | The POLG c.125_127dupGGC variant is predicted to result in an in-frame duplication (p.Arg42dup). This variant has been reported in a patient with keratoconus (described as c.127_128insGGC, Chen et al. 2022. PubMed ID: 35186329), and was reported to be enriched among a study population of individuals with higher self-rated postoperative pain scores (Loke et al. 2019. PubMed ID: 31571979). This variant is reported in 0.051% of alleles in individuals of African descent in gnomAD, which may be too common to be a primary cause of disease. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 09, 2021 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Hereditary spastic paraplegia Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Dec 12, 2016 | - - |
Progressive sclerosing poliodystrophy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 13, 2025 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at