rs1057524249

Positions:

• chr15-89333738-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 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:4
• Conservation: PhyloP100: 4.49

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]

POLGARF (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLG	NM_002693.3	c.17G>C	p.Trp6Ser	missense_variant	2/23	ENST00000268124.11	NP_002684.1
POLG	NM_001126131.2	c.17G>C	p.Trp6Ser	missense_variant	2/23		NP_001119603.1
POLGARF	NM_001406557.1	c.72G>C	p.Leu24Leu	synonymous_variant	2/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLG	ENST00000268124.11	c.17G>C	p.Trp6Ser	missense_variant	2/23	1	NM_002693.3	ENSP00000268124.5
POLGARF	ENST00000706918.1	c.72G>C	p.Leu24Leu	synonymous_variant	1/2			ENSP00000516626.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000153 AC: 2 AN: 130594 Hom.: 0 AF XY: 0.0000140 AC XY: 1 AN XY: 71450

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 SAS 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

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: 0.00000742

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Progressive sclerosing poliodystrophy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	Oct 01, 2018	The NM_002693.2:c.17G>C (NP_002684.1:p.Trp6Ser) [GRCH38: NC_000015.10:g.89333738C>G] variant in POLG gene is interpretated to be a Uncertain Significance based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. BP4:Computational evidence/predictors indicate no impact on the POLG structure, function, or protein-protein interaction. PM2:This variant is absent in key population databases. Based on the evidence criteria codes applied, the variant is suggested to be Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 03, 2022	This sequence change replaces tryptophan, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 6 of the POLG protein (p.Trp6Ser). This variant is present in population databases (no rsID available, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with POLG-related conditions. ClinVar contains an entry for this variant (Variation ID: 391825). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt POLG protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 15, 2020

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Intellectual disability Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

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;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;D
MetaSVM	Uncertain	-0.053	T
MutationAssessor	Benign	1.0	L;L
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.40	N;N
REVEL	Uncertain	0.48
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.58	T;T
Polyphen		0.18	B;B
Vest4		0.65
MutPred		0.48		Loss of catalytic residue at L4 (P = 0.0042);Loss of catalytic residue at L4 (P = 0.0042);
MVP		0.95
MPC		0.44
ClinPred		0.45	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.36
gMVP		0.71

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: rs1057524249; hg19: chr15-89876969;