chr15-89323415-G-A

Position:

• chr15-89323415-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_002693.3(POLG):​c.2254C>T​(p.Leu752Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0112 in 1,610,096 control chromosomes in the GnomAD database, including 183 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.012 (28 hom., cov: 33)
  • Exomes 𝑓: 0.011 (155 hom.)
• Consequence: POLG NM_002693.3 synonymous
• Clinical Significance: Benign reviewed by expert panel B:17
• Conservation: PhyloP100: 2.79

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 15-89323415-G-A is Benign according to our data. Variant chr15-89323415-G-A is described in ClinVar as [Benign]. Clinvar id is 129991.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr15-89323415-G-A is described in Lovd as [Likely_benign]. Variant chr15-89323415-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.79 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0117 (1779/152330) while in subpopulation NFE AF= 0.0137 (933/68036). AF 95% confidence interval is 0.013. There are 28 homozygotes in gnomad4. There are 956 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 28 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLG	NM_002693.3	c.2254C>T	p.Leu752Leu	synonymous_variant	13/23	ENST00000268124.11	NP_002684.1
POLG	NM_001126131.2	c.2254C>T	p.Leu752Leu	synonymous_variant	13/23		NP_001119603.1
POLGARF	NM_001406557.1	c.*1526C>T		3_prime_UTR_variant	13/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLG	ENST00000268124.11	c.2254C>T	p.Leu752Leu	synonymous_variant	13/23	1	NM_002693.3	ENSP00000268124.5

Frequencies

GnomAD3 genomes AF: 0.0117 AC: 1782 AN: 152212 Hom.: 28 Cov.: 33

Gnomad AFR AF: 0.00174

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.00366

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00992

Gnomad FIN AF: 0.0583

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0137

Gnomad OTH AF: 0.00907

GnomAD3 exomes AF: 0.0128 AC: 3212 AN: 251192 Hom.: 55 AF XY: 0.0130 AC XY: 1760 AN XY: 135776

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.00243

Gnomad ASJ exome AF: 0.00814

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00775

Gnomad FIN exome AF: 0.0566

Gnomad NFE exome AF: 0.0132

Gnomad OTH exome AF: 0.0106

GnomAD4 exome AF: 0.0112 AC: 16334 AN: 1457766 Hom.: 155 Cov.: 30 AF XY: 0.0113 AC XY: 8181 AN XY: 725474

Gnomad4 AFR exome AF: 0.000779

Gnomad4 AMR exome AF: 0.00277

Gnomad4 ASJ exome AF: 0.00670

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00675

Gnomad4 FIN exome AF: 0.0542

Gnomad4 NFE exome AF: 0.0108

Gnomad4 OTH exome AF: 0.00886

GnomAD4 genome AF: 0.0117 AC: 1779 AN: 152330 Hom.: 28 Cov.: 33 AF XY: 0.0128 AC XY: 956 AN XY: 74484

Gnomad4 AFR AF: 0.00173

Gnomad4 AMR AF: 0.00366

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00952

Gnomad4 FIN AF: 0.0583

Gnomad4 NFE AF: 0.0137

Gnomad4 OTH AF: 0.00898

Alfa AF: 0.0116 Hom.: 10

Bravo AF: 0.00677

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0116

EpiControl AF: 0.0106

ClinVar

Significance: Benign

Submissions summary: Benign:17

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:6

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 29, 2016	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	POLG: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 26, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 15, 2011	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 03, 2024	- -

Progressive sclerosing poliodystrophy Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, 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.2254C>T (NP_002684.1:p.Leu752=) [GRCH38: NC_000015.10:g.89323415G>A] variant in POLG gene is interpretated to be a Benign based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. BS1:The minor allele frequency of this allele is high for Mitochondrial DNA depletion syndrome 4A (Alpers type). BS2:Observation of the variant in controls is inconsistent with penetrance of Mitochondrial DNA depletion syndrome 4A (Alpers type). BP4:Computational evidence/predictors indicate no impact on the POLG structure, function, or protein-protein interaction. Based on the evidence criteria codes applied, the variant is suggested to be Benign. -

POLG-Related Spectrum Disorders Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 26, 2016

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Mitochondrial disease Benign:1

Benign, reviewed by expert panel

curation

ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen

May 23, 2021

The c.2254 C>T (p.Leu752=) variant in POLG has been reported with an allele frequency in the population at 1.3 % in GnomAD and 6.2% in ExAC (BS1). It is also a synonymous change which is not predicted to impact the protein (BP7). In summary, this variant meets criteria to be classified benign for primary mitochondrial disease inherited in a recessive manner. ntDNA Mitochondrial ACMG-AMP Criteria for POLG applied: BS1, BP7. -

Hereditary spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Feb 26, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	8.5
DANN	Benign	0.70
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs41564016; hg19: chr15-89866646;