15-89326537-A-AC

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 7 publications found

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

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002693.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLG	NM_002693.3	MANE Select	c.1712+74dupG		intron	N/A	NP_002684.1
	POLG	NM_001126131.2		c.1712+74dupG		intron	N/A	NP_001119603.1
	MIR6766	NR_106824.1		n.*201dupG		downstream_gene	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLG	ENST00000268124.11	TSL:1 MANE Select	c.1712+74_1712+75insG		intron	N/A	ENSP00000268124.5
	POLG	ENST00000442287.6	TSL:1	c.1712+74_1712+75insG		intron	N/A	ENSP00000399851.2
	POLG	ENST00000636937.2	TSL:5	c.1712+74_1712+75insG		intron	N/A	ENSP00000516154.1

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

African (AFR) AF: 0.0771 AC: 2501 AN: 32452

American (AMR) AF: 0.333 AC: 14601 AN: 43900

Ashkenazi Jewish (ASJ) AF: 0.374 AC: 9441 AN: 25210

East Asian (EAS) AF: 0.284 AC: 11107 AN: 39148

South Asian (SAS) AF: 0.378 AC: 32074 AN: 84816

European-Finnish (FIN) AF: 0.337 AC: 15006 AN: 44480

Middle Eastern (MID) AF: 0.313 AC: 1660 AN: 5306

European-Non Finnish (NFE) AF: 0.339 AC: 360094 AN: 1061428

Other (OTH) AF: 0.323 AC: 18766 AN: 58090

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

African (AFR) AF: 0.0905 AC: 3758 AN: 41518

American (AMR) AF: 0.300 AC: 4589 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.372 AC: 1290 AN: 3466

East Asian (EAS) AF: 0.306 AC: 1579 AN: 5156

South Asian (SAS) AF: 0.373 AC: 1801 AN: 4828

European-Finnish (FIN) AF: 0.337 AC: 3560 AN: 10550

Middle Eastern (MID) AF: 0.299 AC: 88 AN: 294

European-Non Finnish (NFE) AF: 0.342 AC: 23207 AN: 67948

Other (OTH) AF: 0.278 AC: 588 AN: 2112

Alfa AF: 0.142 Hom.: 328

Bravo AF: 0.258

Asia WGS AF: 0.309 AC: 1072 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.26
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3176183; hg19: chr15-89869768; COSMIC: COSV51519784; COSMIC: COSV51519784;