15-89318535-G-A
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Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_002693.3(POLG):c.3482+6C>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00016 in 1,611,858 control chromosomes in the GnomAD database, including 3 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 0.00056 ( 1 hom., cov: 32)
Exomes 𝑓: 0.00012 ( 2 hom. )
Consequence
POLG
NM_002693.3 splice_donor_region, intron
NM_002693.3 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.0001169
2
Clinical Significance
Conservation
PhyloP100: -0.685
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 -9 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.73).
BP6
Variant 15-89318535-G-A is Benign according to our data. Variant chr15-89318535-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 138760.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, Benign=1, Likely_benign=3}.
BS2
High Homozygotes in GnomAdExome4 at 2 AD,AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLG | NM_002693.3 | c.3482+6C>T | splice_donor_region_variant, intron_variant | ENST00000268124.11 | |||
POLGARF | NM_001406557.1 | c.*2754+6C>T | splice_donor_region_variant, intron_variant | ||||
POLG | NM_001126131.2 | c.3482+6C>T | splice_donor_region_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLG | ENST00000268124.11 | c.3482+6C>T | splice_donor_region_variant, intron_variant | 1 | NM_002693.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000558 AC: 85AN: 152238Hom.: 1 Cov.: 32
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GnomAD3 exomes AF: 0.000231 AC: 58AN: 250808Hom.: 0 AF XY: 0.000221 AC XY: 30AN XY: 135662
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GnomAD4 exome AF: 0.000119 AC: 173AN: 1459502Hom.: 2 Cov.: 31 AF XY: 0.000114 AC XY: 83AN XY: 726106
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GnomAD4 genome AF: 0.000558 AC: 85AN: 152356Hom.: 1 Cov.: 32 AF XY: 0.000604 AC XY: 45AN XY: 74500
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:5
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Progressive sclerosing poliodystrophy Uncertain:1Benign:2
Uncertain significance, criteria provided, single submitter | research | Cardiogenetic Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences | Jul 05, 2019 | - - |
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.3482+6C>T (NP_002684.1:p.=) [GRCH38: NC_000015.10:g.89318535G>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. Based on the evidence criteria codes applied, the variant is suggested to be Likely Benign. - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 03, 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 | Athena Diagnostics | Jun 07, 2021 | - - |
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. - |
Hereditary spastic paraplegia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Oct 01, 2018 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 16, 2017 | - - |
Progressive sclerosing poliodystrophy;C1834846:Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1;C1843851:Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis;C3150914:Mitochondrial DNA depletion syndrome 4b;C4225153:Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Mar 30, 2021 | POLG NM_002693 exon 21 c.3482+6C>T: This variant has not been reported in the literature but is present in 0.1% (35/23996) of African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs55779802). This variant is present in ClinVar (Variation ID:138760). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is an intronic variant with no predicted change in the amino acid sequence but may have an unknown effect on splicing. Further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. - |
Mitochondrial DNA depletion syndrome 4b Benign:1
Likely benign, no assertion criteria provided | clinical testing | Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS) | - | - - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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Calibrated prediction
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at