15-89317458-C-G

Variant names:

• chr15-89317458-C-G
• rs62640037
• NM_002693.3:c.3561G>C

Variant summary

Our verdict is Uncertain significance. The variant received -3 ACMG points: 2P and 5B. PM2 BP7 BS2

This summary comes from the ClinGen Evidence Repository: The c.3561 G>C (p.Arg1187=) variant in POLG is present in population databases 1000 genome 0.03%, ExAC at 0.002%, and gnomAD at 0.002% (PM2; observed < 0.05% frequency). Computational prediction tool Revel unavailable given limited data. This variant was observed in homozygotes in 13 cases in gnomAD and 1 case in ExAC (BS2). This variant is a coding synonymous change (BP7). In summary, there is not sufficient evidence to characterize this variant as pathogenic or benign, therefore it is characterized as a variant of uncertain significance for primary mitochondrial disease inherited in a autosomal recessive manner.ntDNA Mitochondrial ACMG-AMP Criteria for POLG applied: BS2, PM2, BP7. LINK:https://erepo.genome.network/evrepo/ui/classification/CA288989/MONDO:0044970/014

• Frequency:
  • Genomes: 𝑓 0.0073 (16 hom., cov: 32)
  • Exomes 𝑓: 0.00073 (15 hom.)
• Consequence: POLG NM_002693.3 synonymous
• Clinical Significance: Uncertain significance reviewed by expert panel U:1 B:9
• Conservation: PhyloP100: 1.22
• Publications: 3 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: Labcorp Genetics (formerly Invitae), ClinGen, G2P
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Specifications for POLG are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Uncertain_significance. The variant received -3 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: For more information check the summary or visit ClinGen Evidence Repository.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLG	NM_002693.3	MANE Select	c.3561G>C	p.Arg1187Arg	synonymous	Exon 22 of 23	NP_002684.1	P54098
	POLG	NM_001126131.2		c.3561G>C	p.Arg1187Arg	synonymous	Exon 22 of 23	NP_001119603.1	P54098
	FANCI	NM_018193.3		c.*999C>G		downstream_gene	N/A	NP_060663.2	Q9NVI1-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLG	ENST00000268124.11	TSL:1 MANE Select	c.3561G>C	p.Arg1187Arg	synonymous	Exon 22 of 23	ENSP00000268124.5	P54098
	POLG	ENST00000442287.6	TSL:1	c.3561G>C	p.Arg1187Arg	synonymous	Exon 22 of 23	ENSP00000399851.2	P54098
	POLG	ENST00000636937.2	TSL:5	c.3561G>C	p.Arg1187Arg	synonymous	Exon 22 of 23	ENSP00000516154.1	P54098

Frequencies

GnomAD3 genomes AF: 0.00726 AC: 1105 AN: 152148 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.0255

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00177 AC: 445 AN: 251490 AF XY: 0.00121

Gnomad AFR exome AF: 0.0251

Gnomad AMR exome AF: 0.000838

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000727 AC: 1063 AN: 1461778 Hom.: 15 Cov.: 31 AF XY: 0.000619 AC XY: 450 AN XY: 727194

African (AFR) AF: 0.0275 AC: 922 AN: 33480

American (AMR) AF: 0.00110 AC: 49 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111902

Other (OTH) AF: 0.00136 AC: 82 AN: 60392

GnomAD4 genome AF: 0.00728 AC: 1108 AN: 152266 Hom.: 16 Cov.: 32 AF XY: 0.00732 AC XY: 545 AN XY: 74468

African (AFR) AF: 0.0255 AC: 1057 AN: 41528

American (AMR) AF: 0.00242 AC: 37 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68020

Other (OTH) AF: 0.00521 AC: 11 AN: 2112

Alfa AF: 0.00221 Hom.: 3

Bravo AF: 0.00828

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	3	Progressive sclerosing poliodystrophy (3)
-	-	1	Inborn genetic diseases (1)
-	1	-	Mitochondrial disease (1)
-	-	1	not provided (1)
-	-	1	POLG-Related Spectrum Disorders (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	6.5
DANN	Benign	0.81
PhyloP100		1.2
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs62640037; hg19: chr15-89860689; COSMIC: COSV51521853; COSMIC: COSV51521853;