rs2307433

Positions:

• chr15-89321085-G-GCTAC

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]

POLGARF (HGNC:):

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/exons	MANE	Protein	UniProt
POLG	NM_002693.3	c.2734+39_2734+40insGTAG		intron_variant		ENST00000268124.11	NP_002684.1
POLG	NM_001126131.2	c.2734+39_2734+40insGTAG		intron_variant			NP_001119603.1
POLGARF	NM_001406557.1	c.*2006+39_*2006+40insGTAG		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLG	ENST00000268124.11	c.2734+39_2734+40insGTAG		intron_variant		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

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jul 15, 2024

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

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Progressive sclerosing poliodystrophy Benign:1

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.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;