rs61752784

Variant names:

• chr15-89330133-C-G
• rs61752784
• NM_002693.3:c.803G>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP3 BP4_Strong BP6 BS2

The NM_002693.3(POLG):​c.803G>C​(p.Gly268Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00395 in 1,614,062 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0035 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (17 hom.)
• Consequence: POLG NM_002693.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:9 B:10 O:1
• Conservation: PhyloP100: 7.87
• Publications: 33 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]

POLGARF (HGNC:56246): (POLG alternative reading frame) This gene uses the same transcript as the POLG gene but has a CUG start codon and an alternate reading frame that makes a 260 aa protein. This protein is distinct from POLG isoforms and may interact with P32 (also known as C1QBP), a mitochondrial matrix protein thought to be involved in the expression of mitochondrial genome-encoded proteins. POLGARF protein may bind P32 and sequester it in the nucleolus. Interestingly, some disease-causing mutations thought to be in POLG may instead be associated with POLGARF. [provided by RefSeq, May 2022]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.05388558).
• BP6: Variant 15-89330133-C-G is Benign according to our data. Variant chr15-89330133-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 196354.
• BS2: High Homozygotes in GnomAdExome4 at 17 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLG	NM_002693.3	MANE Select	c.803G>C	p.Gly268Ala	missense	Exon 3 of 23	NP_002684.1	P54098
	POLG	NM_001126131.2		c.803G>C	p.Gly268Ala	missense	Exon 3 of 23	NP_001119603.1	P54098
	POLGARF	NM_001430120.1	MANE Select	c.*75G>C		downstream_gene	N/A	NP_001417049.1	A0A3B3IS91

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLG	ENST00000268124.11	TSL:1 MANE Select	c.803G>C	p.Gly268Ala	missense	Exon 3 of 23	ENSP00000268124.5	P54098
	POLG	ENST00000442287.6	TSL:1	c.803G>C	p.Gly268Ala	missense	Exon 3 of 23	ENSP00000399851.2	P54098
	POLG	ENST00000636937.2	TSL:5	c.803G>C	p.Gly268Ala	missense	Exon 3 of 23	ENSP00000516154.1	P54098

Frequencies

GnomAD3 genomes AF: 0.00353 AC: 538 AN: 152224 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000868

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.00634

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00546

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00439

Gnomad OTH AF: 0.00767

GnomAD2 exomes AF: 0.00344 AC: 865 AN: 251312 AF XY: 0.00348

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.00497

Gnomad ASJ exome AF: 0.00585

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00416

Gnomad NFE exome AF: 0.00419

Gnomad OTH exome AF: 0.00733

GnomAD4 exome AF: 0.00400 AC: 5843 AN: 1461720 Hom.: 17 Cov.: 32 AF XY: 0.00395 AC XY: 2871 AN XY: 727180

African (AFR) AF: 0.000597 AC: 20 AN: 33480

American (AMR) AF: 0.00474 AC: 212 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00517 AC: 135 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000371 AC: 32 AN: 86254

European-Finnish (FIN) AF: 0.00436 AC: 232 AN: 53266

Middle Eastern (MID) AF: 0.00451 AC: 26 AN: 5768

European-Non Finnish (NFE) AF: 0.00446 AC: 4958 AN: 1111998

Other (OTH) AF: 0.00378 AC: 228 AN: 60394

GnomAD4 genome AF: 0.00352 AC: 537 AN: 152342 Hom.: 1 Cov.: 32 AF XY: 0.00346 AC XY: 258 AN XY: 74492

African (AFR) AF: 0.000866 AC: 36 AN: 41574

American (AMR) AF: 0.00634 AC: 97 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4826

European-Finnish (FIN) AF: 0.00546 AC: 58 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00439 AC: 299 AN: 68032

Other (OTH) AF: 0.00759 AC: 16 AN: 2108

Alfa AF: 0.00444 Hom.: 2

Bravo AF: 0.00369

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.000682 AC: 3

ESP6500EA AF: 0.00547 AC: 47

ExAC AF: 0.00348 AC: 422

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00431

EpiControl AF: 0.00533

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	2	not provided (6)
-	1	3	not specified (4)
-	-	3	Progressive sclerosing poliodystrophy (3)
-	1	-	Charcot-Marie-Tooth disease axonal type 2U (1)
-	1	-	Hereditary spastic paraplegia (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	POLG-related disorder (2)
-	1	-	POLG-Related Spectrum Disorders (1)
-	1	-	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 (1)
1	-	-	Tip-toe gait (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.50
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.054	T
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		7.9
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MVP		0.98
MPC		0.68
ClinPred		0.030	T
GERP RS		5.5
Varity_R		0.95
gMVP		0.91
Mutation Taster		=89/11	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: rs61752784; hg19: chr15-89873364;