rs2307438

chr15-89317555-A-C

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.3483-19T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.403 in 1,608,966 control chromosomes in the GnomAD database, including 132,575 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (14769 hom., cov: 31)
  • Exomes 𝑓: 0.40 (117806 hom.)
• Consequence: POLG NM_002693.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.383

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=-0.86).
• BP6: Variant 15-89317555-A-C is Benign according to our data. Variant chr15-89317555-A-C is described in ClinVar as [Benign]. Clinvar id is 138763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-89317555-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.513 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLG	NM_002693.3	c.3483-19T>G		intron_variant		ENST00000268124.11
POLGARF	NM_001406557.1	c.*2755-19T>G		intron_variant
POLG	NM_001126131.2	c.3483-19T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLG	ENST00000268124.11	c.3483-19T>G		intron_variant		1	NM_002693.3	P1

Frequencies

GnomAD3 genomes AF: 0.437 AC: 66310 AN: 151604 Hom.: 14747 Cov.: 31

Gnomad AFR AF: 0.518

Gnomad AMI AF: 0.390

Gnomad AMR AF: 0.422

Gnomad ASJ AF: 0.379

Gnomad EAS AF: 0.354

Gnomad SAS AF: 0.390

Gnomad FIN AF: 0.485

Gnomad MID AF: 0.367

Gnomad NFE AF: 0.399

Gnomad OTH AF: 0.413

GnomAD3 exomes AF: 0.421 AC: 105528 AN: 250716 Hom.: 22736 AF XY: 0.417 AC XY: 56514 AN XY: 135614

Gnomad AFR exome AF: 0.515

Gnomad AMR exome AF: 0.499

Gnomad ASJ exome AF: 0.393

Gnomad EAS exome AF: 0.359

Gnomad SAS exome AF: 0.397

Gnomad FIN exome AF: 0.479

Gnomad NFE exome AF: 0.393

Gnomad OTH exome AF: 0.406

GnomAD4 exome AF: 0.399 AC: 581755 AN: 1457244 Hom.: 117806 Cov.: 33 AF XY: 0.399 AC XY: 289157 AN XY: 725206

Gnomad4 AFR exome AF: 0.520

Gnomad4 AMR exome AF: 0.488

Gnomad4 ASJ exome AF: 0.395

Gnomad4 EAS exome AF: 0.339

Gnomad4 SAS exome AF: 0.398

Gnomad4 FIN exome AF: 0.471

Gnomad4 NFE exome AF: 0.391

Gnomad4 OTH exome AF: 0.407

GnomAD4 genome AF: 0.437 AC: 66376 AN: 151722 Hom.: 14769 Cov.: 31 AF XY: 0.443 AC XY: 32825 AN XY: 74138

Gnomad4 AFR AF: 0.518

Gnomad4 AMR AF: 0.421

Gnomad4 ASJ AF: 0.379

Gnomad4 EAS AF: 0.354

Gnomad4 SAS AF: 0.392

Gnomad4 FIN AF: 0.485

Gnomad4 NFE AF: 0.399

Gnomad4 OTH AF: 0.409

Alfa AF: 0.428 Hom.: 3359

Bravo AF: 0.440

Asia WGS AF: 0.376 AC: 1306 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Progressive sclerosing poliodystrophy Benign:3

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.3483-19T>G (NP_002684.1:p.=) [GRCH38: NC_000015.10:g.89317555A>C] 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). 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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Oct 25, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

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

- -

Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 25, 2019

- -

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	-0.86
Cadd	Benign	11
Dann	Benign	0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs2307438; hg19: chr15-89860786; COSMIC: COSV51521392; COSMIC: COSV51521392;