rs2246900

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.3105-36A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.378 in 1,613,776 control chromosomes in the GnomAD database, including 118,208 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.32 ( 8995 hom., cov: 33)

Exomes 𝑓: 0.38 ( 109213 hom. )

Consequence

POLG
NM_002693.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.442

Publications

20 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: 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

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

This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 2 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 15-89319135-T-C is Benign according to our data. Variant chr15-89319135-T-C is described in ClinVar as Benign. ClinVar VariationId is 619492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.391 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLG	NM_002693.3 link	c.3105-36A>G		intron_variant	Intron 19 of 22	ENST00000268124.11	NP_002684.1	P54098E5KNU5
POLG	NM_001126131.2 link	c.3105-36A>G		intron_variant	Intron 19 of 22		NP_001119603.1	P54098E5KNU5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLG	ENST00000268124.11 link	c.3105-36A>G		intron_variant	Intron 19 of 22	1	NM_002693.3	ENSP00000268124.5		P54098

Frequencies

GnomAD3 genomes

AF:

0.324

AC:

49225

AN:

152008

Hom.:

8993

Cov.:

show subpopulations

Gnomad AFR

AF:

0.152

Gnomad AMI

AF:

0.389

Gnomad AMR

AF:

0.328

Gnomad ASJ

AF:

0.371

Gnomad EAS

AF:

0.325

Gnomad SAS

AF:

0.390

Gnomad FIN

AF:

0.483

Gnomad MID

AF:

0.316

Gnomad NFE

AF:

0.395

Gnomad OTH

AF:

0.318

GnomAD2 exomes

AF:

0.374

AC:

94018

AN:

251406

AF XY:

0.381

show subpopulations

Gnomad AFR exome

AF:

0.144

Gnomad AMR exome

AF:

0.371

Gnomad ASJ exome

AF:

0.381

Gnomad EAS exome

AF:

0.326

Gnomad FIN exome

AF:

0.476

Gnomad NFE exome

AF:

0.389

Gnomad OTH exome

AF:

0.376

GnomAD4 exome

AF:

0.383

AC:

559976

AN:

1461650

Hom.:

109213

Cov.:

AF XY:

0.385

AC XY:

279617

AN XY:

727154

show subpopulations

African (AFR)

AF:

0.140

AC:

4675

AN:

33480

American (AMR)

AF:

0.365

AC:

16330

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.385

AC:

10060

AN:

26134

East Asian (EAS)

AF:

0.312

AC:

12388

AN:

39696

South Asian (SAS)

AF:

0.398

AC:

34326

AN:

86252

European-Finnish (FIN)

AF:

0.468

AC:

25021

AN:

53416

Middle Eastern (MID)

AF:

0.340

AC:

1962

AN:

5768

European-Non Finnish (NFE)

AF:

0.389

AC:

432551

AN:

1111792

Other (OTH)

AF:

0.375

AC:

22663

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

21674

43348

65023

86697

108371

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13380

26760

40140

53520

66900

<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:

0.324

AC:

49230

AN:

152126

Hom.:

8995

Cov.:

AF XY:

0.332

AC XY:

24671

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.152

AC:

6309

AN:

41518

American (AMR)

AF:

0.328

AC:

5010

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.371

AC:

1288

AN:

3472

East Asian (EAS)

AF:

0.326

AC:

1681

AN:

5164

South Asian (SAS)

AF:

0.391

AC:

1888

AN:

4826

European-Finnish (FIN)

AF:

0.483

AC:

5112

AN:

10580

Middle Eastern (MID)

AF:

0.316

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.395

AC:

26829

AN:

67966

Other (OTH)

AF:

0.316

AC:

667

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1620

3240

4859

6479

8099

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

506

1012

1518

2024

2530

<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:

0.354

Hom.:

2669

Bravo

AF:

0.307

Asia WGS

AF:

0.333

AC:

1155

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Progressive sclerosing poliodystrophy

Benign:3

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 25, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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.3105-36A>G (NP_002684.1:p.=) [GRCH38: NC_000015.10:g.89319135T>C] 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). BS1:The minor allele frequency of this allele is high for Mitochondrial DNA depletion syndrome 4A (Alpers type). BS2:Observation of the variant in controls is inconsistent with penetrance of 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. -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1

Benign:1

Oct 25, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1

Benign:1

Oct 25, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis

Benign:1

Oct 25, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mitochondrial DNA depletion syndrome 4b

Benign:1

Oct 25, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

7.7

(source)

DANN

Benign

0.71

PhyloP100

0.44

BranchPoint Hunter

2.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over