Variant rs773073959 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_002693.3(POLG):c.1991G>C(p.Gly664Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,461,370 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

POLG
NM_002693.3 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 3.75

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 Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.21438819).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLG	NM_002693.3 linkuse as main transcript	c.1991G>C	p.Gly664Ala	missense_variant	11/23	ENST00000268124.11	NP_002684.1	P54098E5KNU5
POLG	NM_001126131.2 linkuse as main transcript	c.1991G>C	p.Gly664Ala	missense_variant	11/23		NP_001119603.1	P54098E5KNU5
POLGARF	NM_001406557.1 linkuse as main transcript	c.*1263G>C		3_prime_UTR_variant	11/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLG	ENST00000268124.11 linkuse as main transcript	c.1991G>C	p.Gly664Ala	missense_variant	11/23	1	NM_002693.3	ENSP00000268124.5		P54098

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250376

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135382

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000995

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1461370

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726986

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000230

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

POLG-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 05, 2024

The POLG c.1991G>C variant is predicted to result in the amino acid substitution p.Gly664Ala. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0099% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

DANN

Benign

0.87

DEOGEN2

Benign

0.33

T;T

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.10

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.84

.;T

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.21

T;T

MetaSVM

Uncertain

-0.13

MutationAssessor

Benign

2.0

M;M

PrimateAI

Benign

0.40

PROVEAN

Benign

0.22

N;N

REVEL

Uncertain

0.38

Sift

Benign

0.72

T;T

Sift4G

Benign

0.86

T;T

Polyphen

0.13

B;B

Vest4

0.47

MutPred

0.19

Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);

MVP

0.87

MPC

0.19

ClinPred

0.26

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.039

gMVP

0.48

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