chr15-89333177-C-T

Variant names:

• chr15-89333177-C-T
• rs3176162
• NM_002693.3:c.578G>A

Variant summary

Our verdict is Uncertain significance. The variant received -4 ACMG points: 0P and 4B. BS2

This summary comes from the ClinGen Evidence Repository: The c.578G>A (p.Arg193Gln) variant in POLG has been reported with an allele frequency in the population at 0.2 % in African Americans in gnomAD. It is also seen in the homozygous state in 1 individual in gnomAD (BS2). This variant is not reported in the literature and no computational data is available. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a recessive manner. ntDNA Mitochondrial ACMG-AMP Criteria for POLG applied: BS2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA241475/MONDO:0044970/014

• Frequency:
  • Genomes: 𝑓 0.00066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000050 (0 hom.)
• Consequence: POLG NM_002693.3 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:8 B:4
• Conservation: PhyloP100: 0.369
• Publications: 8 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: Uncertain_significance. The variant received -4 ACMG points.

• 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.578G>A	p.Arg193Gln	missense	Exon 2 of 23	NP_002684.1	P54098
	POLGARF	NM_001430120.1	MANE Select	c.633G>A	p.Ala211Ala	synonymous	Exon 1 of 2	NP_001417049.1	A0A3B3IS91
	POLG	NM_001126131.2		c.578G>A	p.Arg193Gln	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.578G>A	p.Arg193Gln	missense	Exon 2 of 23	ENSP00000268124.5	P54098
	POLG	ENST00000442287.6	TSL:1	c.578G>A	p.Arg193Gln	missense	Exon 2 of 23	ENSP00000399851.2	P54098
	POLGARF	ENST00000706918.1	MANE Select	c.633G>A	p.Ala211Ala	synonymous	Exon 1 of 2	ENSP00000516626.1	A0A3B3IS91

Frequencies

GnomAD3 genomes AF: 0.000663 AC: 101 AN: 152228 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00236

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: 0.0000147

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000151 AC: 32 AN: 211358 AF XY: 0.0000954

Gnomad AFR exome AF: 0.00183

Gnomad AMR exome AF: 0.000139

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000195

GnomAD4 exome AF: 0.0000503 AC: 71 AN: 1412880 Hom.: 0 Cov.: 32 AF XY: 0.0000345 AC XY: 24 AN XY: 696658

African (AFR) AF: 0.00182 AC: 58 AN: 31938

American (AMR) AF: 0.000104 AC: 4 AN: 38514

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23508

East Asian (EAS) AF: 0.00 AC: 0 AN: 38950

South Asian (SAS) AF: 0.00 AC: 0 AN: 80590

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50740

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5564

European-Non Finnish (NFE) AF: 0.00000184 AC: 2 AN: 1084962

Other (OTH) AF: 0.000120 AC: 7 AN: 58114

GnomAD4 genome AF: 0.000663 AC: 101 AN: 152346 Hom.: 0 Cov.: 33 AF XY: 0.000497 AC XY: 37 AN XY: 74498

African (AFR) AF: 0.00236 AC: 98 AN: 41584

American (AMR) AF: 0.00 AC: 0 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68028

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000104 Hom.: 0

Bravo AF: 0.000699

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000207 AC: 25

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	4	1	not provided (5)
-	-	2	Progressive sclerosing poliodystrophy (2)
-	1	-	Inborn genetic diseases (1)
-	1	-	Mitochondrial disease (1)
-	-	1	POLG-related disorder (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	0.064
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	1.3	L
PhyloP100		0.37
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	0.76	N
REVEL	Benign	0.16
Sift	Benign	0.42	T
Sift4G	Benign	0.39	T
Polyphen		0.019	B
Vest4		0.089
MVP		0.76
MPC		0.18
ClinPred		0.014	T
GERP RS		2.6
PromoterAI		0.056	Neutral
Varity_R		0.074
gMVP		0.41
Mutation Taster		=97/3	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: rs3176162; hg19: chr15-89876408; COSMIC: COSV51521834; COSMIC: COSV51521834;