rs2307448

chr15-89321860-G-Achr15-89321860-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_002693.3(POLG):c.2481-7C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00454 in 1,612,058 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0047 (21 hom.)
• Consequence: POLG NM_002693.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0002760
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 U:1 B:14
• Conservation: PhyloP100: 0.0640

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 15-89321860-G-A is Benign according to our data. Variant chr15-89321860-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 138747.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-89321860-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLG	NM_002693.3	c.2481-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000268124.11
POLGARF	NM_001406557.1	c.*1753-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
POLG	NM_001126131.2	c.2481-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLG	ENST00000268124.11	c.2481-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_002693.3	P1

Frequencies

GnomAD3 genomes AF: 0.00285 AC: 434 AN: 152152 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00534

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00247 AC: 621 AN: 251400 Hom.: 1 AF XY: 0.00258 AC XY: 351 AN XY: 135888

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.000492

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000915

Gnomad FIN exome AF: 0.000324

Gnomad NFE exome AF: 0.00468

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00472 AC: 6891 AN: 1459788 Hom.: 21 Cov.: 31 AF XY: 0.00468 AC XY: 3396 AN XY: 726384

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.000918

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000963

Gnomad4 FIN exome AF: 0.000693

Gnomad4 NFE exome AF: 0.00586

Gnomad4 OTH exome AF: 0.00323

GnomAD4 genome AF: 0.00285 AC: 434 AN: 152270 Hom.: 1 Cov.: 33 AF XY: 0.00255 AC XY: 190 AN XY: 74448

Gnomad4 AFR AF: 0.00111

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00534

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00421 Hom.: 0

Bravo AF: 0.00270

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00371

EpiControl AF: 0.00539

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Uncertain:1 Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1 Benign:7

Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 24, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 03, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	POLG: BP4, BS2 -
Uncertain significance, flagged submission	clinical testing	Eurofins Ntd Llc (ga)	Sep 17, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 13, 2023	Variant summary: POLG c.2481-7C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. One computational tool predicts no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0025 in 251400 control chromosomes, predominantly at a frequency of 0.0047 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is slightly higher than the estimated maximal expected allele frequency for a pathogenic variant in POLG causing Mitochondrial DNA Depletion Syndrome - POLG Related phenotype (0.0035), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely pathogenic n=1, benign/likely benign n=7, VUS n=2). Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 18, 2013	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. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 23, 2019	- -

Progressive sclerosing poliodystrophy Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 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.2481-7C>T (NP_002684.1:p.=) [GRCH38: NC_000015.10:g.89321860G>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. -

Tip-toe gait Pathogenic:1

Likely pathogenic, flagged submission

clinical testing

Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino

Feb 03, 2021

We conducted a clinical examination of patients about toe walking. The POLG c.2481-7C>T was detected in 5 patients. We also examined a control group of children without toe walking (100 children). In this group this variant could not be identified. -

Hereditary spastic paraplegia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Feb 17, 2021

- -

POLG-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 28, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
Cadd	Benign	2.1
Dann	Benign	0.83
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00028
dbscSNV1_RF	Benign	0.0080
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: rs2307448; hg19: chr15-89865091;