rs201786897
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1
The NM_002693.3(POLG):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000521 in 1,535,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000036 ( 0 hom. )
Consequence
POLG
NM_002693.3 start_lost
NM_002693.3 start_lost
Scores
4
4
1
Clinical Significance
Conservation
PhyloP100: 2.85
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_pathogenic. Variant got 8 ACMG points.
PVS1
?
Start lost variant, no new inframe start found.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLG | NM_002693.3 | c.1A>G | p.Met1? | start_lost | 2/23 | ENST00000268124.11 | |
POLGARF | NM_001406557.1 | c.56A>G | p.His19Arg | missense_variant | 2/23 | ||
POLG | NM_001126131.2 | c.1A>G | p.Met1? | start_lost | 2/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLG | ENST00000268124.11 | c.1A>G | p.Met1? | start_lost | 2/23 | 1 | NM_002693.3 | P1 | |
POLGARF | ENST00000706918.1 | c.56A>G | p.His19Arg | missense_variant | 1/2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152130Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000308 AC: 4AN: 130002Hom.: 0 AF XY: 0.0000281 AC XY: 2AN XY: 71100
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GnomAD4 exome AF: 0.00000362 AC: 5AN: 1382776Hom.: 0 Cov.: 32 AF XY: 0.00000293 AC XY: 2AN XY: 682414
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GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152248Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74436
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Progressive sclerosing poliodystrophy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 26, 2019 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 19, 2022 | This sequence change affects the initiator methionine of the POLG mRNA. The next in-frame methionine is located at codon 78. This variant is present in population databases (rs201786897, gnomAD 0.02%). Disruption of the initiator codon has been observed in individual(s) with Alpers syndrome (PMID: 31665838). ClinVar contains an entry for this variant (Variation ID: 528383). 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:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MutationTaster
Benign
D;D
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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