15-89320697-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.0910

Publications

48 publications found

Variant links:

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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
mitochondrial DNA depletion syndrome 4a
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Ambry Genetics
sensory ataxic neuropathy, dysarthria, and ophthalmoparesis
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, 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

POLG links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

Sel.	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	P54098
	POLG	NM_001126131.2		c.2981+69A>C		intron	N/A	NP_001119603.1	P54098

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
POLG	ENST00000268124.11	TSL:1 MANE Select	c.2981+69A>C	intron	N/A	ENSP00000268124.5	P54098
POLG	ENST00000442287.6	TSL:1	c.2981+69A>C	intron	N/A	ENSP00000399851.2	P54098
POLG	ENST00000636937.2	TSL:5	c.2981+69A>C	intron	N/A	ENSP00000516154.1	P54098

Frequencies

GnomAD3 genomes

AF:

0.467

AC:

70977

AN:

151834

Hom.:

17478

Cov.:

show subpopulations

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

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

17554

35108

52663

70217

87771

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12844

25688

38532

51376

64220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.468

AC:

71045

AN:

151954

Hom.:

17507

Cov.:

AF XY:

0.471

AC XY:

34983

AN XY:

74266

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1886

3772

5659

7545

9431

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

642

1284

1926

2568

3210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.412

Hom.:

58698

Bravo

AF:

0.472

Asia WGS

AF:

0.378

AC:

1315

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

1.3

(source)

DANN

Benign

0.34

PhyloP100

0.091

PromoterAI

0.0061

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over