rs201016638

Variant names:

• chr15-89333621-T-C
• rs201016638
• NM_002693.3:c.134A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002693.3(POLG):​c.134A>G​(p.Gln45Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000552 in 1,599,410 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q45L) has been classified as Uncertain significance. The gene POLG is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0028 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00031 (4 hom.)
• Consequence: POLG NM_002693.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.348
• Publications: 5 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004382491).
• BP6: Variant 15-89333621-T-C is Benign according to our data. Variant chr15-89333621-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 195179.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00282 (429/152088) while in subpopulation AFR AF = 0.00978 (406/41512). AF 95% confidence interval is 0.009. There are 2 homozygotes in GnomAd4. There are 205 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.134A>G	p.Gln45Arg	missense	Exon 2 of 23	NP_002684.1	P54098
	POLGARF	NM_001430120.1	MANE Select	c.189A>G	p.Ala63Ala	synonymous	Exon 1 of 2	NP_001417049.1	A0A3B3IS91
	POLG	NM_001126131.2		c.134A>G	p.Gln45Arg	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.134A>G	p.Gln45Arg	missense	Exon 2 of 23	ENSP00000268124.5	P54098
	POLG	ENST00000442287.6	TSL:1	c.134A>G	p.Gln45Arg	missense	Exon 2 of 23	ENSP00000399851.2	P54098
	POLGARF	ENST00000706918.1	MANE Select	c.189A>G	p.Ala63Ala	synonymous	Exon 1 of 2	ENSP00000516626.1	A0A3B3IS91

Frequencies

GnomAD3 genomes AF: 0.00282 AC: 429 AN: 151972 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00981

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000960

GnomAD2 exomes AF: 0.000672 AC: 150 AN: 223334 AF XY: 0.000607

Gnomad AFR exome AF: 0.00915

Gnomad AMR exome AF: 0.000424

Gnomad ASJ exome AF: 0.00116

Gnomad EAS exome AF: 0.0000595

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000606

Gnomad OTH exome AF: 0.000180

GnomAD4 exome AF: 0.000314 AC: 454 AN: 1447322 Hom.: 4 Cov.: 32 AF XY: 0.000260 AC XY: 187 AN XY: 719782

African (AFR) AF: 0.0100 AC: 332 AN: 33190

American (AMR) AF: 0.000572 AC: 25 AN: 43698

Ashkenazi Jewish (ASJ) AF: 0.000964 AC: 25 AN: 25936

East Asian (EAS) AF: 0.0000508 AC: 2 AN: 39338

South Asian (SAS) AF: 0.0000468 AC: 4 AN: 85508

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47060

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5712

European-Non Finnish (NFE) AF: 0.0000190 AC: 21 AN: 1107076

Other (OTH) AF: 0.000736 AC: 44 AN: 59804

GnomAD4 genome AF: 0.00282 AC: 429 AN: 152088 Hom.: 2 Cov.: 33 AF XY: 0.00276 AC XY: 205 AN XY: 74354

African (AFR) AF: 0.00978 AC: 406 AN: 41512

American (AMR) AF: 0.00118 AC: 18 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

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: 0.00 AC: 0 AN: 67936

Other (OTH) AF: 0.000950 AC: 2 AN: 2106

Alfa AF: 0.00223 Hom.: 0

Bravo AF: 0.00354

ExAC AF: 0.000702 AC: 79

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	2	Progressive sclerosing poliodystrophy (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	POLG-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	5.1
DANN	Benign	0.14
DEOGEN2	Benign	0.20	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.42	T
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.35
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	0.32	N
REVEL	Benign	0.25
Sift	Benign	0.43	T
Sift4G	Benign	0.64	T
Polyphen		0.0	B
Vest4		0.15
MVP		0.59
MPC		0.16
ClinPred		0.0049	T
GERP RS		-0.71
PromoterAI		0.013	Neutral
Varity_R		0.033
gMVP		0.11
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: rs201016638; hg19: chr15-89876852; COSMIC: COSV51521237; COSMIC: COSV51521237;