chr15-89333596-T-TTGC

Position:

• chr15-89333596-T-TTGC

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_002693.3(POLG):​c.158_159insGCA​(p.Gln54dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 1,597,358 control chromosomes in the GnomAD database, including 6,315 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1354 hom., cov: 30)
  • Exomes 𝑓: 0.10 (4961 hom.)
• Consequence: POLG NM_002693.3 inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: -2.20

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:56246): (POLG alternative reading frame) This gene uses the same transcript as the POLG gene but has a CUG start codon and an alternate reading frame that makes a 260 aa protein. This protein is distinct from POLG isoforms and may interact with P32 (also known as C1QBP), a mitochondrial matrix protein thought to be involved in the expression of mitochondrial genome-encoded proteins. POLGARF protein may bind P32 and sequester it in the nucleolus. Interestingly, some disease-causing mutations thought to be in POLG may instead be associated with POLGARF. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 15-89333596-T-TTGC is Benign according to our data. Variant chr15-89333596-T-TTGC is described in ClinVar as [Likely_benign]. Clinvar id is 167522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.195 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLG	NM_002693.3	c.158_159insGCA	p.Gln54dup	inframe_insertion	2/23	ENST00000268124.11	NP_002684.1
POLGARF	NM_001406557.1	c.213_214insGCA	p.Ala71dup	inframe_insertion	2/23		NP_001393486.1
POLG	NM_001126131.2	c.158_159insGCA	p.Gln54dup	inframe_insertion	2/23		NP_001119603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLG	ENST00000268124.11	c.158_159insGCA	p.Gln54dup	inframe_insertion	2/23	1	NM_002693.3	ENSP00000268124	P1
POLGARF	ENST00000706918.1	c.213_214insGCA	p.Ala71dup	inframe_insertion	1/2			ENSP00000516626	P1

Frequencies

GnomAD3 genomes AF: 0.124 AC: 18728 AN: 151570 Hom.: 1351 Cov.: 30

Gnomad AFR AF: 0.198

Gnomad AMI AF: 0.135

Gnomad AMR AF: 0.0888

Gnomad ASJ AF: 0.124

Gnomad EAS AF: 0.0141

Gnomad SAS AF: 0.106

Gnomad FIN AF: 0.0477

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.107

Gnomad OTH AF: 0.121

GnomAD4 exome AF: 0.100 AC: 144743 AN: 1445684 Hom.: 4961 Cov.: 31 AF XY: 0.0993 AC XY: 71362 AN XY: 718820

Gnomad4 AFR exome AF: 0.192

Gnomad4 AMR exome AF: 0.0599

Gnomad4 ASJ exome AF: 0.115

Gnomad4 EAS exome AF: 0.0119

Gnomad4 SAS exome AF: 0.0925

Gnomad4 FIN exome AF: 0.0441

Gnomad4 NFE exome AF: 0.105

Gnomad4 OTH exome AF: 0.101

GnomAD4 genome AF: 0.124 AC: 18748 AN: 151674 Hom.: 1354 Cov.: 30 AF XY: 0.119 AC XY: 8844 AN XY: 74142

Gnomad4 AFR AF: 0.199

Gnomad4 AMR AF: 0.0887

Gnomad4 ASJ AF: 0.124

Gnomad4 EAS AF: 0.0141

Gnomad4 SAS AF: 0.105

Gnomad4 FIN AF: 0.0477

Gnomad4 NFE AF: 0.107

Gnomad4 OTH AF: 0.122

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 30, 2013	- -
Benign, no assertion criteria provided	clinical testing	Eurofins Ntd Llc (ga)	Feb 19, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jul 10, 2015	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not provided Benign:4

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 22, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 03, 2020	This variant is associated with the following publications: (PMID: 23066759, 29190809) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -

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.156_158dup (NP_002684.1:p.Gln53_Gln54insGln) [GRCH38: NC_000015.10:g.89333627_89333629dup] 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. -

Progressive sclerosing poliodystrophy;C1834846:Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1;C1843851:Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis;C3150914:Mitochondrial DNA depletion syndrome 4b;C4225153:Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1;C4551995:Mitochondrial DNA depletion syndrome 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 23, 2021

- -

POLG-Related Spectrum Disorders Benign:1

Benign, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Aug 07, 2018

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 08, 2016

This alteration is classified as 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. -

Hereditary spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 16, 2021

- -

Recessive mitochondrial ataxia syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

Jun 06, 2023

Allele frequency in gnomAD v3.1 is >5% in the African/African American population dataset. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs41550117; hg19: chr15-89876827;