15-89333596-TTGCTGCTGCTGCTGCTGCTGCTGCTGCTGC-TTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGC

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP3BP6_Very_StrongBS2

The NM_001430120.1(POLGARF):​c.205_213dupGCAGCAGCA​(p.Ala69_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 0.00448 in 151,706 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0045 ( 3 hom., cov: 30)
Exomes 𝑓: 0.0013 ( 3 hom. )
Failed GnomAD Quality Control

Consequence

POLGARF
NM_001430120.1 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -2.20
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]
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP3
Nonframeshift variant in repetitive region in NM_001430120.1
BP6
Variant 15-89333596-T-TTGCTGCTGC is Benign according to our data. Variant chr15-89333596-T-TTGCTGCTGC is described in ClinVar as [Likely_benign]. Clinvar id is 206482.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS2
High Homozygotes in GnomAd4 at 3 gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
POLGNM_002693.3 linkc.150_158dupGCAGCAGCA p.Gln51_Gln53dup disruptive_inframe_insertion Exon 2 of 23 ENST00000268124.11 NP_002684.1 P54098E5KNU5
POLGARFNM_001430120.1 linkc.205_213dupGCAGCAGCA p.Ala69_Ala71dup conservative_inframe_insertion Exon 1 of 2 NP_001417049.1
POLGNM_001126131.2 linkc.150_158dupGCAGCAGCA p.Gln51_Gln53dup disruptive_inframe_insertion Exon 2 of 23 NP_001119603.1 P54098E5KNU5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
POLGARFENST00000706918.1 linkc.205_213dupGCAGCAGCA p.Ala69_Ala71dup conservative_inframe_insertion Exon 1 of 2 ENSP00000516626.1 A0A3B3IS91
POLGENST00000268124.11 linkc.150_158dupGCAGCAGCA p.Gln51_Gln53dup disruptive_inframe_insertion Exon 2 of 23 1 NM_002693.3 ENSP00000268124.5 P54098

Frequencies

GnomAD3 genomes
AF:
0.00449
AC:
681
AN:
151602
Hom.:
4
Cov.:
30
show subpopulations
Gnomad AFR
AF:
0.0135
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00118
Gnomad ASJ
AF:
0.000289
Gnomad EAS
AF:
0.00135
Gnomad SAS
AF:
0.00125
Gnomad FIN
AF:
0.00189
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000973
Gnomad OTH
AF:
0.00241
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.00127
AC:
1831
AN:
1446392
Hom.:
3
Cov.:
31
AF XY:
0.00118
AC XY:
847
AN XY:
719194
show subpopulations
Gnomad4 AFR exome
AF:
0.0131
Gnomad4 AMR exome
AF:
0.000934
Gnomad4 ASJ exome
AF:
0.000271
Gnomad4 EAS exome
AF:
0.000634
Gnomad4 SAS exome
AF:
0.000528
Gnomad4 FIN exome
AF:
0.00158
Gnomad4 NFE exome
AF:
0.00100
Gnomad4 OTH exome
AF:
0.00147
GnomAD4 genome
AF:
0.00448
AC:
680
AN:
151706
Hom.:
3
Cov.:
30
AF XY:
0.00440
AC XY:
326
AN XY:
74158
show subpopulations
Gnomad4 AFR
AF:
0.0135
Gnomad4 AMR
AF:
0.00118
Gnomad4 ASJ
AF:
0.000289
Gnomad4 EAS
AF:
0.00136
Gnomad4 SAS
AF:
0.00125
Gnomad4 FIN
AF:
0.00189
Gnomad4 NFE
AF:
0.000973
Gnomad4 OTH
AF:
0.00239

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:13
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:5
Apr 06, 2015
Genetic Services Laboratory, University of Chicago
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Apr 13, 2017
Eurofins Ntd Llc (ga)
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 19, 2014
GeneDx
Significance: Benign
Review Status: flagged submission
Collection Method: clinical testing

The variant is found in POLG panel(s). -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

not provided Benign:5
-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Mar 03, 2015
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 29, 2016
Mayo Clinic Laboratories, Mayo Clinic
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Feb 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

POLG: BS1, BS2 -

Aug 26, 2015
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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
Sep 23, 2021
Fulgent Genetics, Fulgent Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1
Sep 14, 2017
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. -

Progressive sclerosing poliodystrophy Benign:1
Jan 30, 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.

Other links and lift over

dbSNP: rs41550117; hg19: chr15-89876827; API