POLG p.Gln53Pro

Variant names:

• chr15-89333597-T-G
• rs527965158
• NM_002693.3:c.158A>C
• POLG p.Gln53Pro

Your query was ambiguous. Multiple possible variants found:

• chr15-89333597-T-G
• chr15-89333596-TT-AG
• chr15-89333596-TT-GG
• chr15-89333596-TT-CG

Variant summary

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

The NM_002693.3(POLG):​c.158A>C​(p.Gln53Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,310,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q53H) has been classified as Uncertain significance. The gene POLG is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.000049 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: POLG NM_002693.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -2.20
• Publications: 0 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

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

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03366384).

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.158A>C	p.Gln53Pro	missense	Exon 2 of 23	NP_002684.1	P54098
	POLGARF	NM_001430120.1	MANE Select	c.213A>C	p.Ala71Ala	synonymous	Exon 1 of 2	NP_001417049.1	A0A3B3IS91
	POLG	NM_001126131.2		c.158A>C	p.Gln53Pro	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.158A>C	p.Gln53Pro	missense	Exon 2 of 23	ENSP00000268124.5	P54098
	POLG	ENST00000442287.6	TSL:1	c.158A>C	p.Gln53Pro	missense	Exon 2 of 23	ENSP00000399851.2	P54098
	POLGARF	ENST00000706918.1	MANE Select	c.213A>C	p.Ala71Ala	synonymous	Exon 1 of 2	ENSP00000516626.1	A0A3B3IS91

Frequencies

GnomAD3 genomes AF: 0.0000493 AC: 5 AN: 101458 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

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: 0.000104

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000144 AC: 23 AN: 159664 AF XY: 0.000146

Gnomad AFR exome AF: 0.000346

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000262

Gnomad EAS exome AF: 0.0000749

Gnomad FIN exome AF: 0.0000808

Gnomad NFE exome AF: 0.000225

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000174 AC: 21 AN: 1208498 Hom.: 0 Cov.: 31 AF XY: 0.0000116 AC XY: 7 AN XY: 602786

African (AFR) AF: 0.00 AC: 0 AN: 25542

American (AMR) AF: 0.00 AC: 0 AN: 37414

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22676

East Asian (EAS) AF: 0.0000281 AC: 1 AN: 35524

South Asian (SAS) AF: 0.0000398 AC: 3 AN: 75358

European-Finnish (FIN) AF: 0.0000264 AC: 1 AN: 37846

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4974

European-Non Finnish (NFE) AF: 0.0000174 AC: 16 AN: 918730

Other (OTH) AF: 0.00 AC: 0 AN: 50434

GnomAD4 genome AF: 0.0000493 AC: 5 AN: 101518 Hom.: 0 Cov.: 30 AF XY: 0.0000397 AC XY: 2 AN XY: 50362

African (AFR) AF: 0.00 AC: 0 AN: 20180

American (AMR) AF: 0.00 AC: 0 AN: 11224

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2544

East Asian (EAS) AF: 0.00 AC: 0 AN: 4940

South Asian (SAS) AF: 0.00 AC: 0 AN: 3636

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8662

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 204

European-Non Finnish (NFE) AF: 0.000104 AC: 5 AN: 48068

Other (OTH) AF: 0.00 AC: 0 AN: 1410

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Progressive sclerosing poliodystrophy (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.0021	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	5.1
DANN	Benign	0.20
DEOGEN2	Benign	0.19	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.27	T
M_CAP	Benign	0.085	D
MetaRNN	Benign	0.034	T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	-0.55	N
PhyloP100		-2.2
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.58	N
REVEL	Uncertain	0.35
Sift	Benign	0.28	T
Sift4G	Benign	0.27	T
PromoterAI		0.011	Neutral
Varity_R		0.075
gMVP		0.15
Mutation Taster		=100/0	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs527965158; hg19: chr15-89876828;