15-89326537-AC-ACC

Variant names:

• chr15-89326537-A-AC
• rs3176183
• NM_002693.3:c.1712+74dupG

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_002693.3(POLG):​c.1712+74dupG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.327 in 1,546,892 control chromosomes in the GnomAD database, including 85,876 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (6483 hom., cov: 23)
  • Exomes 𝑓: 0.33 (79393 hom.)
• Consequence: POLG NM_002693.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.262

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]

MIR6766 (HGNC:49941): (microRNA 6766) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 15-89326537-A-AC is Benign according to our data. Variant chr15-89326537-A-AC is described in ClinVar as [Benign]. Clinvar id is 1251136.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.359 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLG	NM_002693.3	c.1712+74dupG		intron_variant	Intron 9 of 22	ENST00000268124.11	NP_002684.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLG	ENST00000268124.11	c.1712+74_1712+75insG		intron_variant	Intron 9 of 22	1	NM_002693.3	ENSP00000268124.5

Frequencies

GnomAD3 genomes AF: 0.268 AC: 40777 AN: 151944 Hom.: 6482 Cov.: 23

Gnomad AFR AF: 0.0907

Gnomad AMI AF: 0.347

Gnomad AMR AF: 0.301

Gnomad ASJ AF: 0.372

Gnomad EAS AF: 0.306

Gnomad SAS AF: 0.372

Gnomad FIN AF: 0.337

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.342

Gnomad OTH AF: 0.281

GnomAD4 exome AF: 0.334 AC: 465250 AN: 1394830 Hom.: 79393 AF XY: 0.336 AC XY: 233057 AN XY: 694464

Gnomad4 AFR exome AF: 0.0771

Gnomad4 AMR exome AF: 0.333

Gnomad4 ASJ exome AF: 0.374

Gnomad4 EAS exome AF: 0.284

Gnomad4 SAS exome AF: 0.378

Gnomad4 FIN exome AF: 0.337

Gnomad4 NFE exome AF: 0.339

Gnomad4 OTH exome AF: 0.323

GnomAD4 genome AF: 0.268 AC: 40775 AN: 152062 Hom.: 6483 Cov.: 23 AF XY: 0.274 AC XY: 20372 AN XY: 74332

Gnomad4 AFR AF: 0.0905

Gnomad4 AMR AF: 0.300

Gnomad4 ASJ AF: 0.372

Gnomad4 EAS AF: 0.306

Gnomad4 SAS AF: 0.373

Gnomad4 FIN AF: 0.337

Gnomad4 NFE AF: 0.342

Gnomad4 OTH AF: 0.278

Bravo AF: 0.258

Asia WGS AF: 0.309 AC: 1072 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 35% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 33. Only high quality variants are reported. -

not provided Benign:1

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3176183; hg19: chr15-89869768;