rs369544574

Positions:

chr15-89317460-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_002693.3(POLG):c.3559C>T(p.Arg1187Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000462 in 1,614,036 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R1187R) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00036 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00047 ( 15 hom. )

Consequence

POLG
NM_002693.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:8

Conservation

PhyloP100: 5.15

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014686495).

BP6

Variant 15-89317460-G-A is Benign according to our data. Variant chr15-89317460-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 206570.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Benign=2, Uncertain_significance=2}.

BS2

High Homozygotes in GnomAdExome4 at 15 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
POLG	NM_002693.3 linkuse as main transcript	c.3559C>T	p.Arg1187Trp	missense_variant	22/23	ENST00000268124.11	NP_002684.1
POLGARF	NM_001406557.1 linkuse as main transcript	c.*2831C>T		3_prime_UTR_variant	22/23		NP_001393486.1
POLG	NM_001126131.2 linkuse as main transcript	c.3559C>T	p.Arg1187Trp	missense_variant	22/23		NP_001119603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLG	ENST00000268124.11 linkuse as main transcript	c.3559C>T	p.Arg1187Trp	missense_variant	22/23	1	NM_002693.3	ENSP00000268124	P1

Frequencies

GnomAD3 genomes

AF:

0.000368

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00953

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000966

AC:

243

AN:

251488

Hom.:

AF XY:

0.00135

AC XY:

183

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00741

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000703

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000473

AC:

691

AN:

1461752

Hom.:

Cov.:

AF XY:

0.000664

AC XY:

483

AN XY:

727186

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00670

Gnomad4 FIN exome

AF:

0.0000749

Gnomad4 NFE exome

AF:

0.0000558

Gnomad4 OTH exome

AF:

0.000629

GnomAD4 genome

AF:

0.000361

AC:

AN:

152284

Hom.:

Cov.:

AF XY:

0.000483

AC XY:

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00933

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000332

Hom.:

Bravo

AF:

0.000113

ExAC

AF:

0.00110

AC:

134

Asia WGS

AF:

0.00549

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 22, 2021	This variant is associated with the following publications: (PMID: 26607151, 26341968, 23921535, 16857757, 33469851) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 09, 2018	- -

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 14, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 26, 2016	- -

Progressive sclerosing poliodystrophy

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, 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.3559C>T (NP_002684.1:p.Arg1187Trp) [GRCH38: NC_000015.10:g.89317460G>A] variant in POLG gene is interpretated to be a Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:16857757 . This variant meets the following evidence codes reported in the ACMG-guideline. PM2:This variant is absent in key population databases. PM3:Detected in trans with a pathogenic variant for Mitochondrial DNA depletion syndrome 4A (Alpers type) which is a recessive disorder. PP2:This is a missense variant in POLG with a low rate of benign and high rate of pathogenic missense variations. PP4:Patient's phenotype or family history is highly specific for POLG. Based on the evidence criteria codes applied, the variant is suggested to be Likely Pathogenic. -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 08, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Hereditary spastic paraplegia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Sep 20, 2021

- -

POLG-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 05, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.059

BayesDel_noAF

Uncertain

0.040

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.73

D;D

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.99

.;D

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.015

T;T

MetaSVM

Pathogenic

0.98

MutationAssessor

Benign

1.4

L;L

MutationTaster

Benign

0.92

D;D

PrimateAI

Benign

0.26

PROVEAN

Uncertain

-3.1

D;D

REVEL

Uncertain

0.45

Sift

Uncertain

0.017

D;D

Sift4G

Uncertain

0.021

D;D

Polyphen

0.98

D;D

Vest4

0.51

MutPred

0.33

Gain of ubiquitination at K1191 (P = 0.0554);Gain of ubiquitination at K1191 (P = 0.0554);

MVP

0.98

MPC

0.35

ClinPred

0.11

GERP RS

6.0

Varity_R

0.30

gMVP

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

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