15-89333596-T-TTGCTGC

Position:

chr15-89333596-T-TTGCTGC

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_002693.3(POLG):c.158_159insGCAGCA(p.Gln54_Gln55dup) variant causes a 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 (★★).

Frequency

Genomes: 𝑓 0.039 ( 173 hom., cov: 30)

Exomes 𝑓: 0.029 ( 372 hom. )

Consequence

POLG
NM_002693.3 inframe_insertion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -2.20

Variant links:

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]

POLG links:

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]

POLGARF links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

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/exons	MANE	Protein
POLG	NM_002693.3 linkuse as main transcript	c.158_159insGCAGCA	p.Gln54_Gln55dup	inframe_insertion	2/23	ENST00000268124.11	NP_002684.1
POLGARF	NM_001406557.1 linkuse as main transcript	c.213_214insGCAGCA	p.Ala70_Ala71dup	inframe_insertion	2/23		NP_001393486.1
POLG	NM_001126131.2 linkuse as main transcript	c.158_159insGCAGCA	p.Gln54_Gln55dup	inframe_insertion	2/23		NP_001119603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLG	ENST00000268124.11 linkuse as main transcript	c.158_159insGCAGCA	p.Gln54_Gln55dup	inframe_insertion	2/23	1	NM_002693.3	ENSP00000268124	P1
POLGARF	ENST00000706918.1 linkuse as main transcript	c.213_214insGCAGCA	p.Ala70_Ala71dup	inframe_insertion	1/2			ENSP00000516626	P1

Frequencies

GnomAD3 genomes

AF:

0.0394

AC:

5975

AN:

151578

Hom.:

173

Cov.:

show subpopulations

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.:

AF XY:

0.0278

AC XY:

19979

AN XY:

719178

show subpopulations

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.:

AF XY:

0.0381

AC XY:

2826

AN XY:

74144

show subpopulations

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

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 19, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 26, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Autosomal recessive progressive external ophthalmoplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

May 04, 2023

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

Benign, flagged submission

clinical testing

GeneDx

Dec 23, 2014

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

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 21, 2021

- -

Progressive sclerosing poliodystrophy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over