chr15-89333596-TTGCTGC-T

Position:

• chr15-89333596-TTGCTGC-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The ENST00000268124.11(POLG):​c.153_158del​(p.Gln54_Gln55del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00454 in 1,597,982 control chromosomes in the GnomAD database, including 23 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. Q51Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0040 (2 hom., cov: 30)
  • Exomes 𝑓: 0.0046 (21 hom.)
• Consequence: POLG ENST00000268124.11 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.0750

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 -12 ACMG points.

• BP6: Variant 15-89333596-TTGCTGC-T is Benign according to our data. Variant chr15-89333596-TTGCTGC-T is described in ClinVar as [Likely_benign]. Clinvar id is 167523.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-89333596-TTGCTGC-T is described in Lovd as [Benign]. Variant chr15-89333596-TTGCTGC-T is described in Lovd as [Likely_benign]. Variant chr15-89333596-TTGCTGC-T is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLG	NM_002693.3	c.153_158del	p.Gln54_Gln55del	inframe_deletion	2/23	ENST00000268124.11	NP_002684.1
POLGARF	NM_001406557.1	c.208_213del	p.Ala70_Ala71del	inframe_deletion	2/23		NP_001393486.1
POLG	NM_001126131.2	c.153_158del	p.Gln54_Gln55del	inframe_deletion	2/23		NP_001119603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLG	ENST00000268124.11	c.153_158del	p.Gln54_Gln55del	inframe_deletion	2/23	1	NM_002693.3	ENSP00000268124	P1
POLGARF	ENST00000706918.1	c.208_213del	p.Ala70_Ala71del	inframe_deletion	1/2			ENSP00000516626	P1

Frequencies

GnomAD3 genomes AF: 0.00402 AC: 610 AN: 151602 Hom.: 2 Cov.: 30

Gnomad AFR AF: 0.00158

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.00656

Gnomad ASJ AF: 0.00721

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00549

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00488

Gnomad OTH AF: 0.00723

GnomAD4 exome AF: 0.00459 AC: 6634 AN: 1446276 Hom.: 21 AF XY: 0.00452 AC XY: 3247 AN XY: 719132

Gnomad4 AFR exome AF: 0.00143

Gnomad4 AMR exome AF: 0.00501

Gnomad4 ASJ exome AF: 0.00743

Gnomad4 EAS exome AF: 0.000787

Gnomad4 SAS exome AF: 0.000879

Gnomad4 FIN exome AF: 0.00402

Gnomad4 NFE exome AF: 0.00508

Gnomad4 OTH exome AF: 0.00392

GnomAD4 genome AF: 0.00404 AC: 613 AN: 151706 Hom.: 2 Cov.: 30 AF XY: 0.00379 AC XY: 281 AN XY: 74158

Gnomad4 AFR AF: 0.00157

Gnomad4 AMR AF: 0.00655

Gnomad4 ASJ AF: 0.00721

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00549

Gnomad4 NFE AF: 0.00488

Gnomad4 OTH AF: 0.00859

Bravo AF: 0.00445

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 23, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	POLG: BP3, BS2 -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Eurofins Ntd Llc (ga)	Mar 20, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2013	The variant is found in MITONUC-MITOP panel(s). -

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

Apr 08, 2022

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 22, 2018

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

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;