rs74382477

chr15-89333630-C-Achr15-89333630-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002693.3(POLG):c.125G>T(p.Arg42Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R42Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: POLG NM_002693.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.461

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09083545).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLG	NM_002693.3	c.125G>T	p.Arg42Leu	missense_variant	2/23	ENST00000268124.11
POLGARF	NM_001406557.1	c.180G>T	p.Ala60=	synonymous_variant	2/23
POLG	NM_001126131.2	c.125G>T	p.Arg42Leu	missense_variant	2/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLG	ENST00000268124.11	c.125G>T	p.Arg42Leu	missense_variant	2/23	1	NM_002693.3	P1
POLGARF	ENST00000706918.1	c.180G>T	p.Ala60=	synonymous_variant	1/2			P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	3.0
Dann	Benign	0.68
DEOGEN2	Benign	0.19	T;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.089	N
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.091	T;T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	1.1	N;N
REVEL	Uncertain	0.36
Sift	Benign	0.25	T;T
Sift4G	Benign	0.23	T;T
Polyphen		0.0010	B;B
Vest4		0.16
MutPred		0.18		Loss of solvent accessibility (P = 0.0299);Loss of solvent accessibility (P = 0.0299);
MVP		0.54
MPC		0.19
ClinPred		0.044	T
GERP RS		-0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.033
gMVP		0.30

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: rs74382477; hg19: chr15-89876861;