15-89333596-TTGCTGCTGCTGCTGCTGCTGCTGCTGCTGC-TTGCTGCTGCTGCTGC

Variant names:

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP3BP6_Very_Strong

The NM_001430120.1(POLGARF):c.199_213delGCAGCAGCAGCAGCA(p.Ala67_Ala71del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000144 in 1,598,104 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

POLGARF
NM_001430120.1 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.0750

Variant links:

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]

POLGARF links:

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP3

Nonframeshift variant in repetitive region in NM_001430120.1

BP6

Variant 15-89333596-TTGCTGCTGCTGCTGC-T is Benign according to our data. Variant chr15-89333596-TTGCTGCTGCTGCTGC-T is described in ClinVar as [Likely_benign]. Clinvar id is 206479.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-89333596-TTGCTGCTGCTGCTGC-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLG	NM_002693.3 link	c.144_158delGCAGCAGCAGCAGCA	p.Gln49_Gln53del	disruptive_inframe_deletion	Exon 2 of 23	ENST00000268124.11	NP_002684.1	P54098E5KNU5
POLGARF	NM_001430120.1 link	c.199_213delGCAGCAGCAGCAGCA	p.Ala67_Ala71del	conservative_inframe_deletion	Exon 1 of 2		NP_001417049.1
POLG	NM_001126131.2 link	c.144_158delGCAGCAGCAGCAGCA	p.Gln49_Gln53del	disruptive_inframe_deletion	Exon 2 of 23		NP_001119603.1	P54098E5KNU5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLGARF	ENST00000706918.1 link	c.199_213delGCAGCAGCAGCAGCA	p.Ala67_Ala71del	conservative_inframe_deletion	Exon 1 of 2			ENSP00000516626.1		A0A3B3IS91
POLG	ENST00000268124.11 link	c.144_158delGCAGCAGCAGCAGCA	p.Gln49_Gln53del	disruptive_inframe_deletion	Exon 2 of 23	1	NM_002693.3	ENSP00000268124.5		P54098

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

151604

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000316

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000624

Gnomad FIN

AF:

0.0000947

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000139

AC:

201

AN:

1446396

Hom.:

AF XY:

0.000136

AC XY:

AN XY:

719198

show subpopulations

Gnomad4 AFR exome

AF:

0.000365

Gnomad4 AMR exome

AF:

0.000342

Gnomad4 ASJ exome

AF:

0.0000387

Gnomad4 EAS exome

AF:

0.000279

Gnomad4 SAS exome

AF:

0.0000938

Gnomad4 FIN exome

AF:

0.000125

Gnomad4 NFE exome

AF:

0.000128

Gnomad4 OTH exome

AF:

0.000100

GnomAD4 genome

AF:

0.000191

AC:

AN:

151708

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74160

show subpopulations

Gnomad4 AFR

AF:

0.000315

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000626

Gnomad4 FIN

AF:

0.0000947

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000280

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Oct 06, 2016

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 02, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is found in INFANT-EPI,EPILEPSY,MITONUC-MITOP panel(s). -

not provided

Benign:2

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Inborn genetic diseases

Benign:1

Jan 28, 2019

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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. -

Progressive sclerosing poliodystrophy

Benign:1

Jan 16, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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