chr15-89318535-G-C
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Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_002693.3(POLG):c.3482+6C>G 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 0.0000254 in 1,611,862 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000023 ( 0 hom. )
Consequence
POLG
NM_002693.3 splice_donor_region, intron
NM_002693.3 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.0001612
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 Likely_benign. Variant got -5 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.75).
BP6
Variant 15-89318535-G-C is Benign according to our data. Variant chr15-89318535-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 458716.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLG | NM_002693.3 | c.3482+6C>G | splice_donor_region_variant, intron_variant | ENST00000268124.11 | |||
POLGARF | NM_001406557.1 | c.*2754+6C>G | splice_donor_region_variant, intron_variant | ||||
POLG | NM_001126131.2 | c.3482+6C>G | splice_donor_region_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLG | ENST00000268124.11 | c.3482+6C>G | splice_donor_region_variant, intron_variant | 1 | NM_002693.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000525 AC: 8AN: 152238Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000718 AC: 18AN: 250808Hom.: 0 AF XY: 0.0000663 AC XY: 9AN XY: 135662
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GnomAD4 exome AF: 0.0000226 AC: 33AN: 1459506Hom.: 0 Cov.: 31 AF XY: 0.0000248 AC XY: 18AN XY: 726108
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GnomAD4 genome AF: 0.0000525 AC: 8AN: 152356Hom.: 0 Cov.: 32 AF XY: 0.0000671 AC XY: 5AN XY: 74500
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Progressive sclerosing poliodystrophy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 05, 2022 | This sequence change falls in intron 21 of the POLG gene. It does not directly change the encoded amino acid sequence of the POLG protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs55779802, gnomAD 0.09%). This variant has been observed in individual(s) with clinical features of POLG-related conditions (PMID: 33278787). ClinVar contains an entry for this variant (Variation ID: 458716). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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. - |
POLG-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 09, 2019 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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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