rs2302084

chr15-89319110-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002693.3(POLG):c.3105-11T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.38 in 1,613,784 control chromosomes in the GnomAD database, including 119,307 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (9212 hom., cov: 33)
  • Exomes 𝑓: 0.39 (110095 hom.)
• Consequence: POLG NM_002693.3 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00007278
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 0.867

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 15-89319110-A-G is Benign according to our data. Variant chr15-89319110-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 138754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-89319110-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.392 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLG	NM_002693.3	c.3105-11T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000268124.11
POLGARF	NM_001406557.1	c.*2377-11T>C		splice_polypyrimidine_tract_variant, intron_variant
POLG	NM_001126131.2	c.3105-11T>C		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLG	ENST00000268124.11	c.3105-11T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_002693.3	P1

Frequencies

GnomAD3 genomes AF: 0.332 AC: 50436 AN: 151960 Hom.: 9208 Cov.: 33

Gnomad AFR AF: 0.178

Gnomad AMI AF: 0.387

Gnomad AMR AF: 0.332

Gnomad ASJ AF: 0.373

Gnomad EAS AF: 0.324

Gnomad SAS AF: 0.391

Gnomad FIN AF: 0.483

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.396

Gnomad OTH AF: 0.324

GnomAD3 exomes AF: 0.377 AC: 94663 AN: 251428 Hom.: 18606 AF XY: 0.383 AC XY: 52018 AN XY: 135890

Gnomad AFR exome AF: 0.170

Gnomad AMR exome AF: 0.373

Gnomad ASJ exome AF: 0.383

Gnomad EAS exome AF: 0.327

Gnomad SAS exome AF: 0.397

Gnomad FIN exome AF: 0.476

Gnomad NFE exome AF: 0.390

Gnomad OTH exome AF: 0.378

GnomAD4 exome AF: 0.385 AC: 562801 AN: 1461706 Hom.: 110095 Cov.: 45 AF XY: 0.386 AC XY: 280932 AN XY: 727164

Gnomad4 AFR exome AF: 0.167

Gnomad4 AMR exome AF: 0.367

Gnomad4 ASJ exome AF: 0.387

Gnomad4 EAS exome AF: 0.312

Gnomad4 SAS exome AF: 0.398

Gnomad4 FIN exome AF: 0.468

Gnomad4 NFE exome AF: 0.390

Gnomad4 OTH exome AF: 0.378

GnomAD4 genome AF: 0.332 AC: 50444 AN: 152078 Hom.: 9212 Cov.: 33 AF XY: 0.340 AC XY: 25269 AN XY: 74358

Gnomad4 AFR AF: 0.177

Gnomad4 AMR AF: 0.332

Gnomad4 ASJ AF: 0.373

Gnomad4 EAS AF: 0.324

Gnomad4 SAS AF: 0.393

Gnomad4 FIN AF: 0.483

Gnomad4 NFE AF: 0.396

Gnomad4 OTH AF: 0.321

Alfa AF: 0.370 Hom.: 12629

Bravo AF: 0.316

Asia WGS AF: 0.333 AC: 1155 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 17, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	GeneDx	Jul 01, 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. -

Progressive sclerosing poliodystrophy Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Oct 25, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	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.3105-11T>C (NP_002684.1:p.=) [GRCH38: NC_000015.10:g.89319110A>G] 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. BA1:Minor allele frequency is too high for the Mitochondrial DNA depletion syndrome 4A (Alpers type). 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). Based on the evidence criteria codes applied, the variant is suggested to be Benign. -

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

POLG-Related Spectrum Disorders Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Fanconi anemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

Mitochondrial DNA depletion syndrome 4b Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	6.9
Dann	Benign	0.64

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000073
dbscSNV1_RF	Benign	0.14
SpliceAI score (max)		0.010		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: rs2302084; hg19: chr15-89862341; COSMIC: COSV51521743; COSMIC: COSV51521743;