rs147282197

Variant names:

• chr15-89330258-C-G
• rs147282197
• NM_002693.3:c.678G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM1 BP4_Moderate

The NM_002693.3(POLG):​c.678G>C​(p.Gln226His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000526 in 1,611,630 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00052 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00053 (0 hom.)
• Consequence: POLG NM_002693.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:13 B:5
• Conservation: PhyloP100: 1.16
• 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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_002693.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.07381511).

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.678G>C	p.Gln226His	missense	Exon 3 of 23	NP_002684.1	P54098
	POLGARF	NM_001430120.1	MANE Select	c.733G>C	p.Ala245Pro	missense	Exon 2 of 2	NP_001417049.1	A0A3B3IS91
	POLG	NM_001126131.2		c.678G>C	p.Gln226His	missense	Exon 3 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.678G>C	p.Gln226His	missense	Exon 3 of 23	ENSP00000268124.5	P54098
	POLGARF	ENST00000706918.1	MANE Select	c.733G>C	p.Ala245Pro	missense	Exon 2 of 2	ENSP00000516626.1	A0A3B3IS91
	POLG	ENST00000442287.6	TSL:1	c.678G>C	p.Gln226His	missense	Exon 3 of 23	ENSP00000399851.2	P54098

Frequencies

GnomAD3 genomes AF: 0.000519 AC: 79 AN: 152256 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000896

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000408 AC: 101 AN: 247722 AF XY: 0.000409

Gnomad AFR exome AF: 0.000126

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000340

Gnomad NFE exome AF: 0.000770

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000526 AC: 768 AN: 1459374 Hom.: 0 Cov.: 32 AF XY: 0.000519 AC XY: 377 AN XY: 726014

African (AFR) AF: 0.0000897 AC: 3 AN: 33460

American (AMR) AF: 0.000157 AC: 7 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86214

European-Finnish (FIN) AF: 0.000367 AC: 19 AN: 51802

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5176

European-Non Finnish (NFE) AF: 0.000639 AC: 710 AN: 1111884

Other (OTH) AF: 0.000481 AC: 29 AN: 60294

GnomAD4 genome AF: 0.000519 AC: 79 AN: 152256 Hom.: 0 Cov.: 32 AF XY: 0.000497 AC XY: 37 AN XY: 74380

African (AFR) AF: 0.0000723 AC: 3 AN: 41474

American (AMR) AF: 0.000785 AC: 12 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10630

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

European-Non Finnish (NFE) AF: 0.000896 AC: 61 AN: 68048

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.000578 Hom.: 0

Bravo AF: 0.000457

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000387 AC: 47

EpiCase AF: 0.000436

EpiControl AF: 0.000533

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	5	3	not provided (8)
-	-	2	Progressive sclerosing poliodystrophy (2)
-	1	-	Autism;C0036572:Seizure (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	not specified (1)
-	1	-	POLG-related disorder (1)
-	1	-	POLG-Related Spectrum Disorders (1)
-	1	-	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1 (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)
-	1	-	Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	24
DANN	Uncertain	0.98
Eigen	Benign	-0.23
Eigen_PC	Benign	0.028
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.074	T
PhyloP100		1.2
ClinPred		0.032	T
GERP RS		4.8
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.8
Varity_R		0.34
Mutation Taster		=74/26	disease causing (ClinVar)

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: rs147282197; hg19: chr15-89873489;