chr15-89320697-T-G

Variant names:

• chr15-89320697-T-G
• rs2307449
• NM_002693.3:c.2981+69A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002693.3(POLG):​c.2981+69A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.407 in 1,551,636 control chromosomes in the GnomAD database, including 131,799 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.47 (17507 hom., cov: 32)
  • Exomes 𝑓: 0.40 (114292 hom.)
• Consequence: POLG NM_002693.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0910
• Publications: 48 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 15-89320697-T-G is Benign according to our data. Variant chr15-89320697-T-G is described in ClinVar as Benign. ClinVar VariationId is 1240947.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.629 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.2981+69A>C		intron	N/A	NP_002684.1
	POLG	NM_001126131.2		c.2981+69A>C		intron	N/A	NP_001119603.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLG	ENST00000268124.11	TSL:1 MANE Select	c.2981+69A>C		intron	N/A	ENSP00000268124.5
	POLG	ENST00000442287.6	TSL:1	c.2981+69A>C		intron	N/A	ENSP00000399851.2
	POLG	ENST00000636937.2	TSL:5	c.2981+69A>C		intron	N/A	ENSP00000516154.1

Frequencies

GnomAD3 genomes AF: 0.467 AC: 70977 AN: 151834 Hom.: 17478 Cov.: 32

Gnomad AFR AF: 0.635

Gnomad AMI AF: 0.387

Gnomad AMR AF: 0.399

Gnomad ASJ AF: 0.381

Gnomad EAS AF: 0.340

Gnomad SAS AF: 0.397

Gnomad FIN AF: 0.493

Gnomad MID AF: 0.386

Gnomad NFE AF: 0.398

Gnomad OTH AF: 0.438

GnomAD4 exome AF: 0.401 AC: 560663 AN: 1399682 Hom.: 114292 AF XY: 0.400 AC XY: 279924 AN XY: 699432

African (AFR) AF: 0.640 AC: 20683 AN: 32342

American (AMR) AF: 0.403 AC: 17757 AN: 44074

Ashkenazi Jewish (ASJ) AF: 0.398 AC: 10206 AN: 25674

East Asian (EAS) AF: 0.326 AC: 12815 AN: 39354

South Asian (SAS) AF: 0.405 AC: 34148 AN: 84260

European-Finnish (FIN) AF: 0.479 AC: 22097 AN: 46088

Middle Eastern (MID) AF: 0.407 AC: 1657 AN: 4070

European-Non Finnish (NFE) AF: 0.391 AC: 416984 AN: 1065494

Other (OTH) AF: 0.417 AC: 24316 AN: 58326

GnomAD4 genome AF: 0.468 AC: 71045 AN: 151954 Hom.: 17507 Cov.: 32 AF XY: 0.471 AC XY: 34983 AN XY: 74266

African (AFR) AF: 0.635 AC: 26307 AN: 41416

American (AMR) AF: 0.399 AC: 6089 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.381 AC: 1322 AN: 3468

East Asian (EAS) AF: 0.341 AC: 1760 AN: 5160

South Asian (SAS) AF: 0.398 AC: 1918 AN: 4820

European-Finnish (FIN) AF: 0.493 AC: 5224 AN: 10586

Middle Eastern (MID) AF: 0.374 AC: 110 AN: 294

European-Non Finnish (NFE) AF: 0.398 AC: 27047 AN: 67924

Other (OTH) AF: 0.435 AC: 917 AN: 2110

Alfa AF: 0.412 Hom.: 58698

Bravo AF: 0.472

Asia WGS AF: 0.378 AC: 1315 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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 51% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 47. Only high quality variants are reported.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.3
DANN	Benign	0.34
PhyloP100		0.091
PromoterAI		0.0061	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs2307449; hg19: chr15-89863928; COSMIC: COSV51520172; COSMIC: COSV51520172;