NM_002693.3:c.559G>C

Variant names:

• chr15-89333196-C-G
• rs1555454261
• NM_002693.3:c.559G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002693.3(POLG):​c.559G>C​(p.Val187Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). The gene POLG is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: POLG NM_002693.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 5.97
• Publications: 0 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

Specifications for POLG are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.83

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.559G>C	p.Val187Leu	missense	Exon 2 of 23	NP_002684.1	P54098
	POLGARF	NM_001430120.1	MANE Select	c.614G>C	p.Arg205Pro	missense	Exon 1 of 2	NP_001417049.1	A0A3B3IS91
	POLG	NM_001126131.2		c.559G>C	p.Val187Leu	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.559G>C	p.Val187Leu	missense	Exon 2 of 23	ENSP00000268124.5	P54098
	POLGARF	ENST00000706918.1	MANE Select	c.614G>C	p.Arg205Pro	missense	Exon 1 of 2	ENSP00000516626.1	A0A3B3IS91
	POLG	ENST00000442287.6	TSL:1	c.559G>C	p.Val187Leu	missense	Exon 2 of 23	ENSP00000399851.2	P54098

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1418990 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 700306

African (AFR) AF: 0.00 AC: 0 AN: 32172

American (AMR) AF: 0.00 AC: 0 AN: 39722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24030

East Asian (EAS) AF: 0.00 AC: 0 AN: 38964

South Asian (SAS) AF: 0.00 AC: 0 AN: 81800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50838

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5596

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1087486

Other (OTH) AF: 0.00 AC: 0 AN: 58382

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not specified (1)
-	1	-	Progressive sclerosing poliodystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	26
DANN	Uncertain	1.0
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.83	D
PhyloP100		6.0
ClinPred		1.0	D
GERP RS		4.6
PromoterAI		-0.032	Neutral
Varity_R		0.79

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: rs1555454261; hg19: chr15-89876427;