rs3087374

Positions:

chr15-89316763-C-A

Variant summary

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

The NM_002693.3(POLG):c.3708G>T(p.Gln1236His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0726 in 1,612,344 control chromosomes in the GnomAD database, including 5,095 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.061 ( 411 hom., cov: 32)

Exomes 𝑓: 0.074 ( 4684 hom. )

Consequence

POLG
NM_002693.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:22O:1

Conservation

PhyloP100: 1.22

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:

FANCI (HGNC:25568): (FA complementation group I) The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1 (also called BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (also called BRIP1), FANCL, FANCM and FANCN (also called PALB2). The previously defined group FANCH is the same as FANCA. Fanconi anemia is a genetically heterogeneous recessive disorder characterized by cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defective DNA repair. The members of the Fanconi anemia complementation group do not share sequence similarity; they are related by their assembly into a common nuclear protein complex. This gene encodes the protein for complementation group I. Alternative splicing results in two transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

FANCI 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 (MetaRNN=0.0014915764).

BP6

Variant 15-89316763-C-A is Benign according to our data. Variant chr15-89316763-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 21316.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-89316763-C-A is described in Lovd as [Benign]. Variant chr15-89316763-C-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0825 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLG	NM_002693.3 linkuse as main transcript	c.3708G>T	p.Gln1236His	missense_variant	23/23	ENST00000268124.11	NP_002684.1	P54098E5KNU5
FANCI	NM_001113378.2 linkuse as main transcript	c.*304C>A		3_prime_UTR_variant	38/38	ENST00000310775.12	NP_001106849.1	Q9NVI1-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLG	ENST00000268124.11 linkuse as main transcript	c.3708G>T	p.Gln1236His	missense_variant	23/23	1	NM_002693.3	ENSP00000268124.5		P54098
FANCI	ENST00000310775.12 linkuse as main transcript	c.*304C>A		3_prime_UTR_variant	38/38	1	NM_001113378.2	ENSP00000310842.8		Q9NVI1-3

Frequencies

GnomAD3 genomes

AF:

0.0607

AC:

9240

AN:

152172

Hom.:

411

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0148

Gnomad AMI

AF:

0.135

Gnomad AMR

AF:

0.0458

Gnomad ASJ

AF:

0.0412

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0186

Gnomad FIN

AF:

0.160

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.0843

Gnomad OTH

AF:

0.0583

GnomAD3 exomes

AF:

0.0614

AC:

15410

AN:

250854

Hom.:

724

AF XY:

0.0623

AC XY:

8451

AN XY:

135680

show subpopulations

Gnomad AFR exome

AF:

0.0127

Gnomad AMR exome

AF:

0.0335

Gnomad ASJ exome

AF:

0.0495

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0194

Gnomad FIN exome

AF:

0.148

Gnomad NFE exome

AF:

0.0824

Gnomad OTH exome

AF:

0.0668

GnomAD4 exome

AF:

0.0738

AC:

107789

AN:

1460054

Hom.:

4684

Cov.:

AF XY:

0.0725

AC XY:

52697

AN XY:

726478

show subpopulations

Gnomad4 AFR exome

AF:

0.0126

Gnomad4 AMR exome

AF:

0.0359

Gnomad4 ASJ exome

AF:

0.0490

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.0194

Gnomad4 FIN exome

AF:

0.142

Gnomad4 NFE exome

AF:

0.0815

Gnomad4 OTH exome

AF:

0.0709

GnomAD4 genome

AF:

0.0606

AC:

9236

AN:

152290

Hom.:

411

Cov.:

AF XY:

0.0627

AC XY:

4672

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.0148

Gnomad4 AMR

AF:

0.0457

Gnomad4 ASJ

AF:

0.0412

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0182

Gnomad4 FIN

AF:

0.160

Gnomad4 NFE

AF:

0.0843

Gnomad4 OTH

AF:

0.0582

Alfa

AF:

0.0743

Hom.:

1151

Bravo

AF:

0.0515

TwinsUK

AF:

0.0782

AC:

290

ALSPAC

AF:

0.0742

AC:

286

ESP6500AA

AF:

0.0175

AC:

ESP6500EA

AF:

0.0811

AC:

697

ExAC

AF:

0.0613

AC:

7447

Asia WGS

AF:

0.00751

AC:

AN:

3478

EpiCase

AF:

0.0842

EpiControl

AF:

0.0813

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:22Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:9

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 16, 2016	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 29, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 13, 2024	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided

Benign:3Other:1

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 31541998, 15917273, 21038416, 30255931) -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant classified as Benign and reported on 01-02-2020 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 22, 2016	- -

Fanconi anemia complementation group I

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 26, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Progressive sclerosing poliodystrophy

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 04, 2020	- -
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.3708G>T (NP_002684.1:p.Gln1236His) [GRCH38: NC_000015.10:g.89316763C>A] variant in FANCI 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. 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). BP4:Computational evidence/predictors indicate no impact on the FANCI structure, function, or protein-protein interaction. Based on the evidence criteria codes applied, the variant is suggested to be Benign. -

Progressive sclerosing poliodystrophy;C1834846:Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1;C1843851:Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis;C3150914:Mitochondrial DNA depletion syndrome 4b;C4225153:Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1;C4551995:Mitochondrial DNA depletion syndrome 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 19, 2021

- -

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Jun 24, 2022

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Benign. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with POLG-related mitochondrial disorder. (I) 0108 - This gene is associated with both recessive and dominant disease. Variants are usually inherited in a recessive manner, however progressive external ophthalmoplegia can also be dominant when heterozygous variants are located in the highly conserved active site of motif B of the polymerase domain (PMID: 30451971). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamine to histidine. (I) 0251 - This variant is heterozygous. (I) 0308 - Population frequency for this variant is out of keeping with known incidence of POLG-related mitochondrial disorder (v2: 15912 heterozygotes, 814 homozygotes). (SB) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0805 - This variant has strong previous evidence of being benign in unrelated individuals. This variant has been classified multiple times as benign by clinical diagnostic laboratories and is commonly referred to as a polymorphism in the literature (ClinVar, PMIDs: 22237560, 25488682, 28130605). (SB) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

POLG-Related Spectrum Disorders

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 15, 2016

This alteration is classified as 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. -

Fanconi anemia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Hereditary spastic paraplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 18, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.15

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.25

T;T

Eigen

Uncertain

0.20

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.58

.;T

MetaRNN

Benign

0.0015

T;T

MetaSVM

Uncertain

-0.24

MutationAssessor

Benign

1.1

L;L

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.99

N;N

REVEL

Uncertain

0.36

Sift

Uncertain

0.012

D;D

Sift4G

Uncertain

0.052

T;T

Polyphen

0.80

P;P

Vest4

0.098

MutPred

0.067

Loss of glycosylation at P1239 (P = 0.1381);Loss of glycosylation at P1239 (P = 0.1381);

MPC

0.14

ClinPred

0.0096

GERP RS

5.0

Varity_R

0.16

gMVP

0.49

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