rs121918045

chr15-89333747-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_002693.3(POLG):c.8G>C(p.Arg3Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000723 in 1,382,966 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. R3R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: POLG NM_002693.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.16

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

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-89333747-C-G is Pathogenic according to our data. Variant chr15-89333747-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 13498.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-89333747-C-G is described in UniProt as null. Variant chr15-89333747-C-G is described in UniProt as null.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLG	NM_002693.3	c.8G>C	p.Arg3Pro	missense_variant	2/23	ENST00000268124.11
POLGARF	NM_001406557.1	c.63G>C	p.Pro21=	synonymous_variant	2/23
POLG	NM_001126131.2	c.8G>C	p.Arg3Pro	missense_variant	2/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLG	ENST00000268124.11	c.8G>C	p.Arg3Pro	missense_variant	2/23	1	NM_002693.3	P1
POLGARF	ENST00000706918.1	c.63G>C	p.Pro21=	synonymous_variant	1/2			P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.23e-7 AC: 1 AN: 1382966 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 682508

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.27e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2001

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.38	T;T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.84	D
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.61	D;D
MetaSVM	Uncertain	0.33	D
MutationAssessor	Benign	1.1	L;L
MutationTaster	Benign	0.99	A;A
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.1	N;N
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.025	D;D
Polyphen		0.97	D;D
Vest4		0.39
MutPred		0.75		Gain of ubiquitination at K8 (P = 0.0338);Gain of ubiquitination at K8 (P = 0.0338);
MVP		0.90
MPC		0.43
ClinPred		0.94	D
GERP RS		4.8
Varity_R		0.65
gMVP		0.52

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

Publications

LitVar

Other links and lift over

dbSNP: rs121918045; hg19: chr15-89876978;