rs2307433

Variant names:

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

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.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
• Publications: 19 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]

POLG Gene-Disease associations (from GenCC):

• progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• mitochondrial DNA depletion syndrome 4a

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Orphanet, G2P
• sensory ataxic neuropathy, dysarthria, and ophthalmoparesis

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, G2P
• autosomal dominant progressive external ophthalmoplegia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive progressive external ophthalmoplegia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial neurogastrointestinal encephalomyopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• recessive mitochondrial ataxia syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• spinocerebellar ataxia with epilepsy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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

GnomAD2 exomes AF: 0.492 AC: 123336 AN: 250888 AF XY: 0.488

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 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

African (AFR) AF: 0.800 AC: 26794 AN: 33478

American (AMR) AF: 0.452 AC: 20192 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.496 AC: 12961 AN: 26134

East Asian (EAS) AF: 0.412 AC: 16351 AN: 39700

South Asian (SAS) AF: 0.487 AC: 41996 AN: 86256

European-Finnish (FIN) AF: 0.519 AC: 27714 AN: 53376

Middle Eastern (MID) AF: 0.488 AC: 2811 AN: 5764

European-Non Finnish (NFE) AF: 0.463 AC: 515261 AN: 1111816

Other (OTH) AF: 0.493 AC: 29744 AN: 60392

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

African (AFR) AF: 0.788 AC: 32546 AN: 41324

American (AMR) AF: 0.472 AC: 7204 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.483 AC: 1676 AN: 3470

East Asian (EAS) AF: 0.433 AC: 2235 AN: 5160

South Asian (SAS) AF: 0.482 AC: 2328 AN: 4826

European-Finnish (FIN) AF: 0.523 AC: 5473 AN: 10472

Middle Eastern (MID) AF: 0.476 AC: 140 AN: 294

European-Non Finnish (NFE) AF: 0.471 AC: 31917 AN: 67826

Other (OTH) AF: 0.524 AC: 1107 AN: 2112

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

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.33
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs2307433; hg19: chr15-89864316;