rs2307433

Variant names:

• chr15-89321085-G-GCTAC
• rs2307433
• NM_002693.3:c.2734+39_2734+40insGTAG

Variant summary

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

The NM_002693.3(POLG):​c.2734+39_2734+40insGTAG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.483 in 1,613,304 control chromosomes in the GnomAD database, including 192,450 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (25414 hom., cov: 0)
  • Exomes 𝑓: 0.47 (167036 hom.)
• Consequence: POLG NM_002693.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.325

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 15-89321085-G-GCTAC is Benign according to our data. Variant chr15-89321085-G-GCTAC is described in ClinVar as [Benign]. Clinvar id is 619386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.78 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLG	NM_002693.3	c.2734+39_2734+40insGTAG		intron_variant	Intron 17 of 22	ENST00000268124.11	NP_002684.1
POLG	NM_001126131.2	c.2734+39_2734+40insGTAG		intron_variant	Intron 17 of 22		NP_001119603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLG	ENST00000268124.11	c.2734+39_2734+40insGTAG		intron_variant	Intron 17 of 22	1	NM_002693.3	ENSP00000268124.5

Frequencies

GnomAD3 genomes AF: 0.561 AC: 85012 AN: 151550 Hom.: 25369 Cov.: 0

Gnomad AFR AF: 0.787

Gnomad AMI AF: 0.520

Gnomad AMR AF: 0.472

Gnomad ASJ AF: 0.483

Gnomad EAS AF: 0.432

Gnomad SAS AF: 0.483

Gnomad FIN AF: 0.523

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.471

Gnomad OTH AF: 0.529

GnomAD3 exomes AF: 0.492 AC: 123336 AN: 250888 Hom.: 31209 AF XY: 0.488 AC XY: 66268 AN XY: 135668

Gnomad AFR exome AF: 0.794

Gnomad AMR exome AF: 0.450

Gnomad ASJ exome AF: 0.491

Gnomad EAS exome AF: 0.431

Gnomad SAS exome AF: 0.487

Gnomad FIN exome AF: 0.525

Gnomad NFE exome AF: 0.466

Gnomad OTH exome AF: 0.480

GnomAD4 exome AF: 0.475 AC: 693824 AN: 1461638 Hom.: 167036 Cov.: 37 AF XY: 0.474 AC XY: 344925 AN XY: 727106

Gnomad4 AFR exome AF: 0.800

Gnomad4 AMR exome AF: 0.452

Gnomad4 ASJ exome AF: 0.496

Gnomad4 EAS exome AF: 0.412

Gnomad4 SAS exome AF: 0.487

Gnomad4 FIN exome AF: 0.519

Gnomad4 NFE exome AF: 0.463

Gnomad4 OTH exome AF: 0.493

GnomAD4 genome AF: 0.561 AC: 85097 AN: 151666 Hom.: 25414 Cov.: 0 AF XY: 0.562 AC XY: 41641 AN XY: 74092

Gnomad4 AFR AF: 0.788

Gnomad4 AMR AF: 0.472

Gnomad4 ASJ AF: 0.483

Gnomad4 EAS AF: 0.433

Gnomad4 SAS AF: 0.482

Gnomad4 FIN AF: 0.523

Gnomad4 NFE AF: 0.471

Gnomad4 OTH AF: 0.524

Alfa AF: 0.525 Hom.: 3609

Bravo AF: 0.572

Asia WGS AF: 0.471 AC: 1637 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

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 60% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 56. 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

- -

Progressive sclerosing poliodystrophy Benign:1

Oct 01, 2018

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NM_002693.2:c.2734+39_2734+40insGTAG (NP_002684.1:p.=) [GRCH38: NC_000015.10:g.89321087_89321088insACCT] variant in POLG gene is interpretated to be a Benign based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. BA1:Minor allele frequency is too high for the 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 Benign. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs2307433; hg19: chr15-89864316;