NM_002693.3:c.17G>C

Variant names:

• chr15-89333738-C-G
• rs1057524249
• NM_002693.3:c.17G>C

Variant summary

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

The NM_002693.3(POLG):​c.17G>C​(p.Trp6Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000578 in 1,383,188 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000058 (0 hom.)
• Consequence: POLG NM_002693.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 4.49
• 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

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

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.17G>C	p.Trp6Ser	missense	Exon 2 of 23	NP_002684.1
	POLGARF	NM_001430120.1	MANE Select	c.72G>C	p.Leu24Leu	synonymous	Exon 1 of 2	NP_001417049.1
	POLG	NM_001126131.2		c.17G>C	p.Trp6Ser	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.17G>C	p.Trp6Ser	missense	Exon 2 of 23	ENSP00000268124.5
	POLG	ENST00000442287.6	TSL:1	c.17G>C	p.Trp6Ser	missense	Exon 2 of 23	ENSP00000399851.2
	POLGARF	ENST00000706918.1	MANE Select	c.72G>C	p.Leu24Leu	synonymous	Exon 1 of 2	ENSP00000516626.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000153 AC: 2 AN: 130594 AF XY: 0.0000140

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000404

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000578 AC: 8 AN: 1383188 Hom.: 0 Cov.: 32 AF XY: 0.00000879 AC XY: 6 AN XY: 682652

African (AFR) AF: 0.00 AC: 0 AN: 31576

American (AMR) AF: 0.00 AC: 0 AN: 35700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25140

East Asian (EAS) AF: 0.00 AC: 0 AN: 35722

South Asian (SAS) AF: 0.00 AC: 0 AN: 79356

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5674

European-Non Finnish (NFE) AF: 0.00000742 AC: 8 AN: 1078536

Other (OTH) AF: 0.00 AC: 0 AN: 57852

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	Progressive sclerosing poliodystrophy (3)
-	1	-	Intellectual disability (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.024
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.75	T
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Uncertain	-0.053	T
MutationAssessor	Benign	1.0	L
PhyloP100		4.5
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.40	N
REVEL	Uncertain	0.48
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.58	T
Polyphen		0.18	B
Vest4		0.65
MutPred		0.48		Loss of catalytic residue at L4 (P = 0.0042)
MVP		0.95
MPC		0.44
ClinPred		0.45	T
GERP RS		4.8
PromoterAI		-0.0033	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.36
gMVP		0.71
Mutation Taster		=89/11	polymorphism

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: rs1057524249; hg19: chr15-89876969;