15-89333630-C-A

Variant names:

• chr15-89333630-C-A
• rs74382477
• NM_002693.3:c.125G>T

Variant summary

Our verdict is Uncertain significance. The variant received 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. 13/22 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 Likely benign.

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

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

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLG	NM_002693.3	MANE Select	c.125G>T	p.Arg42Leu	missense	Exon 2 of 23	NP_002684.1
	POLGARF	NM_001430120.1	MANE Select	c.180G>T	p.Ala60Ala	synonymous	Exon 1 of 2	NP_001417049.1
	POLG	NM_001126131.2		c.125G>T	p.Arg42Leu	missense	Exon 2 of 23	NP_001119603.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLG	ENST00000268124.11	TSL:1 MANE Select	c.125G>T	p.Arg42Leu	missense	Exon 2 of 23	ENSP00000268124.5
	POLG	ENST00000442287.6	TSL:1	c.125G>T	p.Arg42Leu	missense	Exon 2 of 23	ENSP00000399851.2
	POLGARF	ENST00000706918.1	MANE Select	c.180G>T	p.Ala60Ala	synonymous	Exon 1 of 2	ENSP00000516626.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.089	N
LIST_S2	Benign	0.37	T
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.091	T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.46
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	1.1	N
REVEL	Uncertain	0.36
Sift	Benign	0.25	T
Sift4G	Benign	0.23	T
Polyphen		0.0010	B
Vest4		0.16
MutPred		0.18		Loss of solvent accessibility (P = 0.0299)
MVP		0.54
MPC		0.19
ClinPred		0.044	T
GERP RS		-0.80
PromoterAI		-0.025	Neutral
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

Other links and lift over

dbSNP: rs74382477; hg19: chr15-89876861;