rs1555452607
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_002693.3(POLG):c.3091_3092del(p.Glu1031AsnfsTer15) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
POLG
NM_002693.3 frameshift
NM_002693.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.38
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 15-89319239-TTC-T is Pathogenic according to our data. Variant chr15-89319239-TTC-T is described in ClinVar as [Pathogenic]. Clinvar id is 458710.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLG | NM_002693.3 | c.3091_3092del | p.Glu1031AsnfsTer15 | frameshift_variant | 19/23 | ENST00000268124.11 | |
POLGARF | NM_001406557.1 | c.*2363_*2364del | 3_prime_UTR_variant | 19/23 | |||
POLG | NM_001126131.2 | c.3091_3092del | p.Glu1031AsnfsTer15 | frameshift_variant | 19/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLG | ENST00000268124.11 | c.3091_3092del | p.Glu1031AsnfsTer15 | frameshift_variant | 19/23 | 1 | NM_002693.3 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Progressive sclerosing poliodystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 26, 2017 | For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in POLG are known to be pathogenic (PMID: 18546365). This variant has not been reported in the literature in individuals with a POLG-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Glu1031Asnfs*15) in the POLG gene. It is expected to result in an absent or disrupted protein product. - |
Computational scores
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Calibrated prediction
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Prediction
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at