NM_002693.3:c.3597C>A

Variant names:

• chr15-89317422-G-T
• rs2307443
• NM_002693.3:c.3597C>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_002693.3(POLG):​c.3597C>A​(p.Thr1199Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0101 in 1,613,984 control chromosomes in the GnomAD database, including 118 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Synonymous variant affecting the same amino acid position (i.e. T1199T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0074 (3 hom., cov: 32)
  • Exomes 𝑓: 0.010 (115 hom.)
• Consequence: POLG NM_002693.3 synonymous
• Clinical Significance: Benign reviewed by expert panel B:15
• Conservation: PhyloP100: -0.700
• Publications: 7 publications found

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]

FANCI Gene-Disease associations (from GenCC):

• Fanconi anemia complementation group I

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 15-89317422-G-T is Benign according to our data. Variant chr15-89317422-G-T is described in ClinVar as Benign. ClinVar VariationId is 138766.Status of the report is reviewed_by_expert_panel, 3 stars.
• BP7: Synonymous conserved (PhyloP=-0.7 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00736 (1120/152204) while in subpopulation NFE AF = 0.0112 (759/68014). AF 95% confidence interval is 0.0105. There are 3 homozygotes in GnomAd4. There are 534 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002693.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLG	NM_002693.3	MANE Select	c.3597C>A	p.Thr1199Thr	synonymous	Exon 22 of 23	NP_002684.1
	POLG	NM_001126131.2		c.3597C>A	p.Thr1199Thr	synonymous	Exon 22 of 23	NP_001119603.1
	FANCI	NM_018193.3		c.*963G>T		downstream_gene	N/A	NP_060663.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLG	ENST00000268124.11	TSL:1 MANE Select	c.3597C>A	p.Thr1199Thr	synonymous	Exon 22 of 23	ENSP00000268124.5
	POLG	ENST00000442287.6	TSL:1	c.3597C>A	p.Thr1199Thr	synonymous	Exon 22 of 23	ENSP00000399851.2
	POLG	ENST00000636937.2	TSL:5	c.3597C>A	p.Thr1199Thr	synonymous	Exon 22 of 23	ENSP00000516154.1

Frequencies

GnomAD3 genomes AF: 0.00736 AC: 1120 AN: 152086 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00198

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.0135

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0160

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0112

Gnomad OTH AF: 0.00766

GnomAD2 exomes AF: 0.00788 AC: 1981 AN: 251490 AF XY: 0.00800

Gnomad AFR exome AF: 0.00141

Gnomad AMR exome AF: 0.00194

Gnomad ASJ exome AF: 0.0125

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0127

Gnomad NFE exome AF: 0.0119

Gnomad OTH exome AF: 0.00684

GnomAD4 exome AF: 0.0104 AC: 15255 AN: 1461780 Hom.: 115 Cov.: 31 AF XY: 0.00998 AC XY: 7255 AN XY: 727202

African (AFR) AF: 0.00125 AC: 42 AN: 33478

American (AMR) AF: 0.00203 AC: 91 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0133 AC: 348 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00274 AC: 236 AN: 86258

European-Finnish (FIN) AF: 0.0119 AC: 638 AN: 53418

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.0120 AC: 13397 AN: 1111904

Other (OTH) AF: 0.00821 AC: 496 AN: 60394

GnomAD4 genome AF: 0.00736 AC: 1120 AN: 152204 Hom.: 3 Cov.: 32 AF XY: 0.00718 AC XY: 534 AN XY: 74416

African (AFR) AF: 0.00198 AC: 82 AN: 41508

American (AMR) AF: 0.00222 AC: 34 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0135 AC: 47 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4814

European-Finnish (FIN) AF: 0.0160 AC: 170 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0112 AC: 759 AN: 68014

Other (OTH) AF: 0.00758 AC: 16 AN: 2112

Alfa AF: 0.00901 Hom.: 7

Bravo AF: 0.00614

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00900

EpiControl AF: 0.00978

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:5

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

Significance: Benign

Review Status: no assertion criteria provided

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

Jul 20, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 26, 2012

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:4

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 19, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Sep 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

POLG: BP4, BP7, BS1, BS2

Progressive sclerosing poliodystrophy Benign:2

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.3597C>A (NP_002684.1:p.Thr1199=) [GRCH38: NC_000015.10:g.89317422G>T] variant in POLG 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 POLG structure, function, or protein-protein interaction. BP7:The variant is silent with non predicted splice impact. Based on the evidence criteria codes applied, the variant is suggested to be Benign.

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

POLG-Related Spectrum Disorders Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

Inborn genetic diseases Benign:1

May 26, 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.

Mitochondrial disease Benign:1

May 06, 2021

ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The c.3597C>A (p.T1199=) variant in POLG is present in population databases ExAC at 1.269 (BA1; observed > 1% frequency). Computational prediction tool Revel unavailable given limited data. This variant was observed in homozygotes in 17 cases in gnomAD and 5 case in ExAC (BS2). This variant is a coding synonymous change (BP7). In summary, there is sufficient evidence to characterized this variant as a benign for primary mitochondrial disease inherited in an autosomal recessive manner. ntDNA Mitochondrial ACMG-AMP Criteria for POLG applied: BA1, BS2, BP7.

Hereditary spastic paraplegia Benign:1

Jun 06, 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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	5.0
DANN	Benign	0.77
PhyloP100		-0.70
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs2307443; hg19: chr15-89860653;