chr15-89328789-G-A
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Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2
The NM_002693.3(POLG):c.1066C>T(p.Leu356Leu) variant causes a synonymous change. The variant allele was found at a frequency of 0.0000843 in 1,614,152 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000081 ( 2 hom. )
Consequence
POLG
NM_002693.3 synonymous
NM_002693.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 5.65
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 Benign. Variant got -7 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.4).
BP6
Variant 15-89328789-G-A is Benign according to our data. Variant chr15-89328789-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 138772.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=5, Uncertain_significance=3}.
BS2
High Homozygotes in GnomAdExome4 at 2 AD,AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
POLG | NM_002693.3 | c.1066C>T | p.Leu356Leu | synonymous_variant | 5/23 | ENST00000268124.11 | NP_002684.1 | |
POLG | NM_001126131.2 | c.1066C>T | p.Leu356Leu | synonymous_variant | 5/23 | NP_001119603.1 | ||
POLGARF | NM_001406557.1 | c.*338C>T | 3_prime_UTR_variant | 5/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
POLG | ENST00000268124.11 | c.1066C>T | p.Leu356Leu | synonymous_variant | 5/23 | 1 | NM_002693.3 | ENSP00000268124.5 |
Frequencies
GnomAD3 genomes AF: 0.000118 AC: 18AN: 152254Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000199 AC: 50AN: 251342Hom.: 0 AF XY: 0.000169 AC XY: 23AN XY: 135858
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GnomAD4 exome AF: 0.0000807 AC: 118AN: 1461780Hom.: 2 Cov.: 33 AF XY: 0.0000646 AC XY: 47AN XY: 727180
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GnomAD4 genome AF: 0.000118 AC: 18AN: 152372Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8AN XY: 74512
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:6
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 18, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jul 01, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Mar 01, 2023 | BP4 - |
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 07, 2013 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 03, 2024 | - - |
Progressive sclerosing poliodystrophy Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine | Oct 01, 2018 | The NM_002693.2:c.1066C>T (NP_002684.1:p.Leu356=) [GRCH38: NC_000015.10:g.89328789G>A] variant in POLG gene is interpretated to be a Likely Benign based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. BS1:The minor allele frequency of this allele is high for Mitochondrial DNA depletion syndrome 4A (Alpers type). BP4:Computational evidence/predictors indicate no impact on the POLG structure, function, or protein-protein interaction. BP7:The variant is silent with non predicted splice impact. Based on the evidence criteria codes applied, the variant is suggested to be Likely Benign. - |
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | - - |
POLG-Related Spectrum Disorders Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 11, 2018 | 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. - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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