rs2246900

Positions:

Variant summary

Our verdict is Benign. Variant got -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

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 links:

POLGARF (HGNC:):

POLGARF links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

This place is a probable branch point but likely benign (scored 2 / 10). 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 id is 619492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-89319135-T-C is described in Lovd as [Benign].

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein	UniProt
POLG	NM_002693.3 linkuse as main transcript	c.3105-36A>G	intron_variant	ENST00000268124.11	NP_002684.1	P54098E5KNU5
POLG	NM_001126131.2 linkuse as main transcript	c.3105-36A>G	intron_variant		NP_001119603.1	P54098E5KNU5
POLGARF	NM_001406557.1 linkuse as main transcript	c.*2377-36A>G	intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLG	ENST00000268124.11 linkuse as main transcript	c.3105-36A>G		intron_variant		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

GnomAD3 exomes

AF:

0.374

AC:

94018

AN:

251406

Hom.:

18436

AF XY:

0.381

AC XY:

51751

AN XY:

135884

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 SAS exome

AF:

0.397

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

Gnomad4 AFR exome

AF:

0.140

Gnomad4 AMR exome

AF:

0.365

Gnomad4 ASJ exome

AF:

0.385

Gnomad4 EAS exome

AF:

0.312

Gnomad4 SAS exome

AF:

0.398

Gnomad4 FIN exome

AF:

0.468

Gnomad4 NFE exome

AF:

0.389

Gnomad4 OTH exome

AF:

0.375

GnomAD4 genome

AF:

0.324

AC:

49230

AN:

152126

Hom.:

8995

Cov.:

AF XY:

0.332

AC XY:

24671

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.152

Gnomad4 AMR

AF:

0.328

Gnomad4 ASJ

AF:

0.371

Gnomad4 EAS

AF:

0.326

Gnomad4 SAS

AF:

0.391

Gnomad4 FIN

AF:

0.483

Gnomad4 NFE

AF:

0.395

Gnomad4 OTH

AF:

0.316

Alfa

AF:

0.358

Hom.:

2654

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

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Oct 25, 2021	- -
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.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. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

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 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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

Mitochondrial DNA depletion syndrome 4b

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

7.7

DANN

Benign

0.71

BranchPoint Hunter

2.0

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over