ENST00000706918.1:c.208_213dupGCAGCA

Variant names:

• chr15-89333596-T-TTGCTGC
• rs41550117
• ENST00000706918.1:c.208_213dupGCAGCA

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 2P and 17B. PM1 BP3 BP6_Very_Strong BA1

The ENST00000706918.1(POLGARF):​c.208_213dupGCAGCA​(p.Ala70_Ala71dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0296 in 1,598,052 control chromosomes in the GnomAD database, including 545 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A71A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.039 (173 hom., cov: 30)
  • Exomes 𝑓: 0.029 (372 hom.)
• Consequence: POLGARF ENST00000706918.1 conservative_inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -2.20

Genes affected

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]

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 -15 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 12 benign, 9 uncertain in ENST00000706918.1
• BP3: Nonframeshift variant in repetitive region in ENST00000706918.1
• BP6: Variant 15-89333596-T-TTGCTGC is Benign according to our data. Variant chr15-89333596-T-TTGCTGC is described in ClinVar as [Likely_benign]. Clinvar id is 206484.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0739 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLG	NM_002693.3	c.153_158dupGCAGCA	p.Gln52_Gln53dup	disruptive_inframe_insertion	Exon 2 of 23	ENST00000268124.11	NP_002684.1
POLGARF	NM_001430120.1	c.208_213dupGCAGCA	p.Ala70_Ala71dup	conservative_inframe_insertion	Exon 1 of 2		NP_001417049.1
POLG	NM_001126131.2	c.153_158dupGCAGCA	p.Gln52_Gln53dup	disruptive_inframe_insertion	Exon 2 of 23		NP_001119603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLGARF	ENST00000706918.1	c.208_213dupGCAGCA	p.Ala70_Ala71dup	conservative_inframe_insertion	Exon 1 of 2			ENSP00000516626.1
POLG	ENST00000268124.11	c.153_158dupGCAGCA	p.Gln52_Gln53dup	disruptive_inframe_insertion	Exon 2 of 23	1	NM_002693.3	ENSP00000268124.5

Frequencies

GnomAD3 genomes AF: 0.0394 AC: 5975 AN: 151578 Hom.: 173 Cov.: 30

Gnomad AFR AF: 0.0763

Gnomad AMI AF: 0.00773

Gnomad AMR AF: 0.0322

Gnomad ASJ AF: 0.00779

Gnomad EAS AF: 0.00155

Gnomad SAS AF: 0.0112

Gnomad FIN AF: 0.0131

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0298

Gnomad OTH AF: 0.0385

GnomAD4 exome AF: 0.0286 AC: 41298 AN: 1446370 Hom.: 372 Cov.: 31 AF XY: 0.0278 AC XY: 19979 AN XY: 719178

Gnomad4 AFR exome AF: 0.0738

Gnomad4 AMR exome AF: 0.0173

Gnomad4 ASJ exome AF: 0.00851

Gnomad4 EAS exome AF: 0.00104

Gnomad4 SAS exome AF: 0.0144

Gnomad4 FIN exome AF: 0.0118

Gnomad4 NFE exome AF: 0.0310

Gnomad4 OTH exome AF: 0.0282

GnomAD4 genome AF: 0.0394 AC: 5974 AN: 151682 Hom.: 173 Cov.: 30 AF XY: 0.0381 AC XY: 2826 AN XY: 74144

Gnomad4 AFR AF: 0.0761

Gnomad4 AMR AF: 0.0322

Gnomad4 ASJ AF: 0.00779

Gnomad4 EAS AF: 0.00155

Gnomad4 SAS AF: 0.0113

Gnomad4 FIN AF: 0.0131

Gnomad4 NFE AF: 0.0298

Gnomad4 OTH AF: 0.0382

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 26, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 28, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 19, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive progressive external ophthalmoplegia Benign:1

May 04, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

African/African American population allele frequency is 7.411% (rs41550117, 3143/41176 alleles, 127 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.5.1, this variant is classified as BENIGN. Following criteria are met: BA1 -

not specified Benign:1

Dec 23, 2014

GeneDx

Significance: Benign

Review Status: flagged submission

Collection Method: clinical testing

The variant is found in CHILD-EPI panel(s). -

Inborn genetic diseases Benign:1

Jan 08, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Dec 21, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Progressive sclerosing poliodystrophy Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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;