rs2302084

Positions:

chr15-89319110-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002693.3(POLG):c.3105-11T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.38 in 1,613,784 control chromosomes in the GnomAD database, including 119,307 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.33 ( 9212 hom., cov: 33)

Exomes 𝑓: 0.39 ( 110095 hom. )

Consequence

POLG
NM_002693.3 splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.00007278

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: 0.867

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

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 15-89319110-A-G is Benign according to our data. Variant chr15-89319110-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 138754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-89319110-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.392 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein
POLG	NM_002693.3 linkuse as main transcript	c.3105-11T>C	splice_polypyrimidine_tract_variant, intron_variant	ENST00000268124.11	NP_002684.1
POLGARF	NM_001406557.1 linkuse as main transcript	c.*2377-11T>C	splice_polypyrimidine_tract_variant, intron_variant		NP_001393486.1
POLG	NM_001126131.2 linkuse as main transcript	c.3105-11T>C	splice_polypyrimidine_tract_variant, intron_variant		NP_001119603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLG	ENST00000268124.11 linkuse as main transcript	c.3105-11T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_002693.3	ENSP00000268124	P1

Frequencies

GnomAD3 genomes

AF:

0.332

AC:

50436

AN:

151960

Hom.:

9208

Cov.:

show subpopulations

Gnomad AFR

AF:

0.178

Gnomad AMI

AF:

0.387

Gnomad AMR

AF:

0.332

Gnomad ASJ

AF:

0.373

Gnomad EAS

AF:

0.324

Gnomad SAS

AF:

0.391

Gnomad FIN

AF:

0.483

Gnomad MID

AF:

0.316

Gnomad NFE

AF:

0.396

Gnomad OTH

AF:

0.324

GnomAD3 exomes

AF:

0.377

AC:

94663

AN:

251428

Hom.:

18606

AF XY:

0.383

AC XY:

52018

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.170

Gnomad AMR exome

AF:

0.373

Gnomad ASJ exome

AF:

0.383

Gnomad EAS exome

AF:

0.327

Gnomad SAS exome

AF:

0.397

Gnomad FIN exome

AF:

0.476

Gnomad NFE exome

AF:

0.390

Gnomad OTH exome

AF:

0.378

GnomAD4 exome

AF:

0.385

AC:

562801

AN:

1461706

Hom.:

110095

Cov.:

AF XY:

0.386

AC XY:

280932

AN XY:

727164

show subpopulations

Gnomad4 AFR exome

AF:

0.167

Gnomad4 AMR exome

AF:

0.367

Gnomad4 ASJ exome

AF:

0.387

Gnomad4 EAS exome

AF:

0.312

Gnomad4 SAS exome

AF:

0.398

Gnomad4 FIN exome

AF:

0.468

Gnomad4 NFE exome

AF:

0.390

Gnomad4 OTH exome

AF:

0.378

GnomAD4 genome

AF:

0.332

AC:

50444

AN:

152078

Hom.:

9212

Cov.:

AF XY:

0.340

AC XY:

25269

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.177

Gnomad4 AMR

AF:

0.332

Gnomad4 ASJ

AF:

0.373

Gnomad4 EAS

AF:

0.324

Gnomad4 SAS

AF:

0.393

Gnomad4 FIN

AF:

0.483

Gnomad4 NFE

AF:

0.396

Gnomad4 OTH

AF:

0.321

Alfa

AF:

0.370

Hom.:

12629

Bravo

AF:

0.316

Asia WGS

AF:

0.333

AC:

1155

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 17, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 01, 2011	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
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 52% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 48. Only high quality variants are reported. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Progressive sclerosing poliodystrophy

Benign:3

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.3105-11T>C (NP_002684.1:p.=) [GRCH38: NC_000015.10:g.89319110A>G] 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). Based on the evidence criteria codes applied, the variant is suggested to be Benign. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Oct 25, 2021	- -

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

- -

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

- -

POLG-Related Spectrum Disorders

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Fanconi anemia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

-0.80

CADD

Benign

6.9

DANN

Benign

0.64

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000073

dbscSNV1_RF

Benign

0.14

SpliceAI score (max)

0.010

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