15-89333723-C-T

Variant names:

• chr15-89333723-C-T
• rs765472726
• NM_002693.3:c.32G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_002693.3(POLG):​c.32G>A​(p.Gly11Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000486 in 1,536,106 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G11A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00051 (1 hom.)
• Consequence: POLG NM_002693.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:15 B:1
• Conservation: PhyloP100: 0.239
• Publications: 10 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011898369).

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.32G>A	p.Gly11Asp	missense	Exon 2 of 23	NP_002684.1	P54098
	POLGARF	NM_001430120.1	MANE Select	c.87G>A	p.Arg29Arg	synonymous	Exon 1 of 2	NP_001417049.1	A0A3B3IS91
	POLG	NM_001126131.2		c.32G>A	p.Gly11Asp	missense	Exon 2 of 23	NP_001119603.1	P54098

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLG	ENST00000268124.11	TSL:1 MANE Select	c.32G>A	p.Gly11Asp	missense	Exon 2 of 23	ENSP00000268124.5	P54098
	POLG	ENST00000442287.6	TSL:1	c.32G>A	p.Gly11Asp	missense	Exon 2 of 23	ENSP00000399851.2	P54098
	POLGARF	ENST00000706918.1	MANE Select	c.87G>A	p.Arg29Arg	synonymous	Exon 1 of 2	ENSP00000516626.1	A0A3B3IS91

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152188 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000168 AC: 22 AN: 130892 AF XY: 0.000168

Gnomad AFR exome AF: 0.000161

Gnomad AMR exome AF: 0.0000409

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000404

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000512 AC: 708 AN: 1383918 Hom.: 1 Cov.: 32 AF XY: 0.000477 AC XY: 326 AN XY: 683090

African (AFR) AF: 0.000127 AC: 4 AN: 31616

American (AMR) AF: 0.0000560 AC: 2 AN: 35738

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25148

East Asian (EAS) AF: 0.00 AC: 0 AN: 35756

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79448

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33830

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5644

European-Non Finnish (NFE) AF: 0.000625 AC: 674 AN: 1078880

Other (OTH) AF: 0.000467 AC: 27 AN: 57858

GnomAD4 genome AF: 0.000250 AC: 38 AN: 152188 Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14 AN XY: 74346

African (AFR) AF: 0.000121 AC: 5 AN: 41448

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000456 AC: 31 AN: 68026

Other (OTH) AF: 0.000955 AC: 2 AN: 2094

Alfa AF: 0.000324 Hom.: 0

Bravo AF: 0.000261

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.000169 AC: 13

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	6	-	not provided (6)
-	2	-	POLG-related disorder (2)
-	1	1	Progressive sclerosing poliodystrophy (2)
-	1	-	Hereditary spastic paraplegia (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	Intellectual disability (1)
-	1	-	not specified (1)
-	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;C4551995:Mitochondrial DNA depletion syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.81	L
PhyloP100		0.24
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.25	N
REVEL	Uncertain	0.45
Sift	Uncertain	0.0090	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0	B
Vest4		0.39
MVP		0.61
MPC		0.20
ClinPred		0.040	T
GERP RS		0.34
PromoterAI		0.048	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.15
gMVP		0.49
Mutation Taster		=35/65	disease causing

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: rs765472726; hg19: chr15-89876954; COSMIC: COSV51524197; COSMIC: COSV51524197;