NM_002693.3:c.3105-36A>G

Variant names:

• chr15-89319135-T-C
• rs2246900
• NM_002693.3:c.3105-36A>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.3105-36A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.378 in 1,613,776 control chromosomes in the GnomAD database, including 118,208 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.32 (8995 hom., cov: 33)
  • Exomes 𝑓: 0.38 (109213 hom.)
• Consequence: POLG NM_002693.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.442

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 2 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 15-89319135-T-C is Benign according to our data. Variant chr15-89319135-T-C is described in ClinVar as [Benign]. Clinvar id is 619492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-89319135-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.391 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLG	NM_002693.3	c.3105-36A>G		intron_variant	Intron 19 of 22	ENST00000268124.11	NP_002684.1
POLG	NM_001126131.2	c.3105-36A>G		intron_variant	Intron 19 of 22		NP_001119603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLG	ENST00000268124.11	c.3105-36A>G		intron_variant	Intron 19 of 22	1	NM_002693.3	ENSP00000268124.5

Frequencies

GnomAD3 genomes AF: 0.324 AC: 49225 AN: 152008 Hom.: 8993 Cov.: 33

Gnomad AFR AF: 0.152

Gnomad AMI AF: 0.389

Gnomad AMR AF: 0.328

Gnomad ASJ AF: 0.371

Gnomad EAS AF: 0.325

Gnomad SAS AF: 0.390

Gnomad FIN AF: 0.483

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.395

Gnomad OTH AF: 0.318

GnomAD3 exomes AF: 0.374 AC: 94018 AN: 251406 Hom.: 18436 AF XY: 0.381 AC XY: 51751 AN XY: 135884

Gnomad AFR exome AF: 0.144

Gnomad AMR exome AF: 0.371

Gnomad ASJ exome AF: 0.381

Gnomad EAS exome AF: 0.326

Gnomad SAS exome AF: 0.397

Gnomad FIN exome AF: 0.476

Gnomad NFE exome AF: 0.389

Gnomad OTH exome AF: 0.376

GnomAD4 exome AF: 0.383 AC: 559976 AN: 1461650 Hom.: 109213 Cov.: 41 AF XY: 0.385 AC XY: 279617 AN XY: 727154

Gnomad4 AFR exome AF: 0.140

Gnomad4 AMR exome AF: 0.365

Gnomad4 ASJ exome AF: 0.385

Gnomad4 EAS exome AF: 0.312

Gnomad4 SAS exome AF: 0.398

Gnomad4 FIN exome AF: 0.468

Gnomad4 NFE exome AF: 0.389

Gnomad4 OTH exome AF: 0.375

GnomAD4 genome AF: 0.324 AC: 49230 AN: 152126 Hom.: 8995 Cov.: 33 AF XY: 0.332 AC XY: 24671 AN XY: 74368

Gnomad4 AFR AF: 0.152

Gnomad4 AMR AF: 0.328

Gnomad4 ASJ AF: 0.371

Gnomad4 EAS AF: 0.326

Gnomad4 SAS AF: 0.391

Gnomad4 FIN AF: 0.483

Gnomad4 NFE AF: 0.395

Gnomad4 OTH AF: 0.316

Alfa AF: 0.358 Hom.: 2654

Bravo AF: 0.307

Asia WGS AF: 0.333 AC: 1155 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Progressive sclerosing poliodystrophy Benign:3

Oct 25, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 01, 2018

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NM_002693.2:c.3105-36A>G (NP_002684.1:p.=) [GRCH38: NC_000015.10:g.89319135T>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). 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. -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Oct 25, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 51% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 47. Only high quality variants are reported. -

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

Oct 25, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis Benign:1

Oct 25, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mitochondrial DNA depletion syndrome 4b Benign:1

Oct 25, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	7.7
DANN	Benign	0.71
BranchPoint Hunter		2.0

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: rs2246900; hg19: chr15-89862366; COSMIC: COSV51521755; COSMIC: COSV51521755;