chr15-89330256-C-T

Position:

chr15-89330256-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_002693.3(POLG):c.680G>A(p.Arg227Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,459,604 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

POLG
NM_002693.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 6.08

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.876

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
POLG	NM_002693.3 linkuse as main transcript	c.680G>A	p.Arg227Gln	missense_variant	3/23	ENST00000268124.11	NP_002684.1
POLGARF	NM_001406557.1 linkuse as main transcript	c.735G>A	p.Ala245=	synonymous_variant	3/23		NP_001393486.1
POLG	NM_001126131.2 linkuse as main transcript	c.680G>A	p.Arg227Gln	missense_variant	3/23		NP_001119603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLG	ENST00000268124.11 linkuse as main transcript	c.680G>A	p.Arg227Gln	missense_variant	3/23	1	NM_002693.3	ENSP00000268124	P1
POLGARF	ENST00000706918.1 linkuse as main transcript	c.735G>A	p.Ala245=	synonymous_variant	2/2			ENSP00000516626	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000403

AC:

AN:

247992

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134560

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000895

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1459604

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

726124

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000508

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Jun 28, 2021

- -

Progressive sclerosing poliodystrophy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 07, 2023

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 227 of the POLG protein (p.Arg227Gln). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of POLG-related conditions (PMID: 30290626). ClinVar contains an entry for this variant (Variation ID: 2435149). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on POLG protein function. This variant disrupts the p.Arg227 amino acid residue in POLG. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12707443, 16621917, 16957900, 19307547, 22277967, 25281868). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.31

T;T

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

.;D

M_CAP

Uncertain

0.10

MetaRNN

Pathogenic

0.88

D;D

MetaSVM

Uncertain

0.68

MutationAssessor

Uncertain

2.5

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.66

N;N

REVEL

Pathogenic

0.72

Sift

Benign

0.34

T;T

Sift4G

Benign

0.72

T;T

Polyphen

1.0

D;D

Vest4

0.76

MutPred

0.73

Loss of MoRF binding (P = 0.1187);Loss of MoRF binding (P = 0.1187);

MVP

0.96

MPC

0.71

ClinPred

0.75

GERP RS

5.9

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.8

Varity_R

0.28

gMVP

0.82

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