rs3087374

Variant names:

• chr15-89316763-C-A
• rs3087374
• NM_002693.3:c.3708G>T

Your query was ambiguous. Multiple possible variants found:

• chr15-89316763-C-A
• chr15-89316763-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:23 O:1
• Conservation: PhyloP100: 1.22

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]

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]

ACMG classification

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 rank	MANE	Protein	UniProt
POLG	NM_002693.3	c.3708G>T	p.Gln1236His	missense_variant	Exon 23 of 23	ENST00000268124.11	NP_002684.1
FANCI	NM_001113378.2	c.*304C>A		3_prime_UTR_variant	Exon 38 of 38	ENST00000310775.12	NP_001106849.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLG	ENST00000268124.11	c.3708G>T	p.Gln1236His	missense_variant	Exon 23 of 23	1	NM_002693.3	ENSP00000268124.5
FANCI	ENST00000310775.12	c.*304C>A		3_prime_UTR_variant	Exon 38 of 38	1	NM_001113378.2	ENSP00000310842.8

Frequencies

GnomAD3 genomes AF: 0.0607 AC: 9240 AN: 152172 Hom.: 411 Cov.: 32

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

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.: 30 AF XY: 0.0725 AC XY: 52697 AN XY: 726478

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.: 32 AF XY: 0.0627 AC XY: 4672 AN XY: 74472

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: 77

ESP6500EA AF: 0.0811 AC: 697

ExAC AF: 0.0613 AC: 7447

Asia WGS AF: 0.00751 AC: 26 AN: 3478

EpiCase AF: 0.0842

EpiControl AF: 0.0813

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:23 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:10

Mar 16, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 26, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 29, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 13, 2024

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:3 Other:1

Feb 22, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 31541998, 15917273, 21038416, 30255931) -

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

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. -

Fanconi anemia complementation group I Benign:2

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Oct 26, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Progressive sclerosing poliodystrophy Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 01, 2018

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Nov 19, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

POLG-Related Spectrum Disorders Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1 Benign:1

Jun 24, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Inborn genetic diseases Benign:1

Mar 15, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary spastic paraplegia Benign:1

Dec 18, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T;T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.58	.;T
MetaRNN	Benign	0.0015	T;T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	1.1	L;L
PrimateAI	Benign	0.29	T
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	T
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

Other links and lift over

dbSNP: rs3087374; hg19: chr15-89859994; COSMIC: COSV105090738; COSMIC: COSV105090738;