Variant rs758130 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_002693.3(POLG):c.660-290T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.366 in 152,024 control chromosomes in the GnomAD database, including 10,490 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.37 ( 10490 hom., cov: 32)

Consequence

POLG
NM_002693.3 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -2.96

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:56246): (POLG alternative reading frame) This gene uses the same transcript as the POLG gene but has a CUG start codon and an alternate reading frame that makes a 260 aa protein. This protein is distinct from POLG isoforms and may interact with P32 (also known as C1QBP), a mitochondrial matrix protein thought to be involved in the expression of mitochondrial genome-encoded proteins. POLGARF protein may bind P32 and sequester it in the nucleolus. Interestingly, some disease-causing mutations thought to be in POLG may instead be associated with POLGARF. [provided by RefSeq, May 2022]

POLGARF links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 15-89330566-A-G is Benign according to our data. Variant chr15-89330566-A-G is described in ClinVar as [Benign]. Clinvar id is 680713.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.394 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
POLG	NM_002693.3 link	c.660-290T>C	intron_variant	Intron 2 of 22	ENST00000268124.11	NP_002684.1	P54098E5KNU5
POLG	NM_001126131.2 link	c.660-290T>C	intron_variant	Intron 2 of 22		NP_001119603.1	P54098E5KNU5
POLGARF	NM_001430120.1 link	c.715-290T>C	intron_variant	Intron 1 of 1		NP_001417049.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLG	ENST00000268124.11 link	c.660-290T>C		intron_variant	Intron 2 of 22	1	NM_002693.3	ENSP00000268124.5		P54098
POLGARF	ENST00000706918.1 link	c.715-290T>C		intron_variant	Intron 1 of 1			ENSP00000516626.1		A0A3B3IS91

Frequencies

GnomAD3 genomes

AF:

0.366

AC:

55661

AN:

151906

Hom.:

10489

Cov.:

show subpopulations

Gnomad AFR

AF:

0.288

Gnomad AMI

AF:

0.389

Gnomad AMR

AF:

0.358

Gnomad ASJ

AF:

0.375

Gnomad EAS

AF:

0.323

Gnomad SAS

AF:

0.391

Gnomad FIN

AF:

0.490

Gnomad MID

AF:

0.326

Gnomad NFE

AF:

0.398

Gnomad OTH

AF:

0.362

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.366

AC:

55669

AN:

152024

Hom.:

10490

Cov.:

AF XY:

0.373

AC XY:

27721

AN XY:

74298

show subpopulations

Gnomad4 AFR

AF:

0.287

Gnomad4 AMR

AF:

0.357

Gnomad4 ASJ

AF:

0.375

Gnomad4 EAS

AF:

0.323

Gnomad4 SAS

AF:

0.392

Gnomad4 FIN

AF:

0.490

Gnomad4 NFE

AF:

0.398

Gnomad4 OTH

AF:

0.359

Alfa

AF:

0.382

Hom.:

11479

Bravo

AF:

0.356

Asia WGS

AF:

0.340

AC:

1180

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.029

DANN

Benign

0.27

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

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