rs796052881

chr15-89324118-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_002693.3(POLG):c.2059A>G(p.Ile687Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,702 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: POLG NM_002693.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 0.0620

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:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09113166).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLG	NM_002693.3	c.2059A>G	p.Ile687Val	missense_variant	11/23	ENST00000268124.11
POLGARF	NM_001406557.1	c.*1331A>G		3_prime_UTR_variant	11/23
POLG	NM_001126131.2	c.2059A>G	p.Ile687Val	missense_variant	11/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLG	ENST00000268124.11	c.2059A>G	p.Ile687Val	missense_variant	11/23	1	NM_002693.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461702 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727148

Gnomad4 AFR exome AF: 0.0000299

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: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000658 Hom.: 0

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;C1834846:Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1;C1843851:Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis;C3150914:Mitochondrial DNA depletion syndrome 4b;C4225153:Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1;C4551995:Mitochondrial DNA depletion syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

POLG-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 27, 2023

The POLG c.2059A>G variant is predicted to result in the amino acid substitution p.Ile687Val. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 04, 2014

p.Ile687Val (ATA>GTA): c.2059 A>G in exon 11 of the POLG gene (NM_002693.2). A variant of unknown significance has been identified in the POLG gene. The I687V variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The I687V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved across species, and Valine is observed at this position in multiple species in evolution. In silico analysis predicts this variant likely does not alter the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in INFANT-EPI panel(s). -

Progressive sclerosing poliodystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 10, 2023

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 687 of the POLG protein (p.Ile687Val). This variant is not present in population databases (gnomAD no frequency). 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: 206508). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	4.8
Dann	Benign	0.42
DEOGEN2	Benign	0.20	T;T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.66	D
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.091	T;T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	-0.41	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.12	N;N
REVEL	Benign	0.27
Sift	Benign	1.0	T;T
Sift4G	Benign	0.78	T;T
Polyphen		0.0	B;B
Vest4		0.079
MVP		0.60
MPC		0.13
ClinPred		0.030	T
GERP RS		-0.13
Varity_R		0.012
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs796052881; hg19: chr15-89867349;