15-89333596-TTGCTGCTGCTGCTGC-T

Position:

• chr15-89333596-TTGCTGCTGCTGCTGC-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_002693.3(POLG):​c.144_158del​(p.Gln51_Gln55del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000144 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: POLG NM_002693.3 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• 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 -8 ACMG points.

• 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/exons	MANE	Protein	UniProt
POLG	NM_002693.3	c.144_158del	p.Gln51_Gln55del	inframe_deletion	2/23	ENST00000268124.11	NP_002684.1
POLGARF	NM_001406557.1	c.199_213del	p.Ala67_Ala71del	inframe_deletion	2/23		NP_001393486.1
POLG	NM_001126131.2	c.144_158del	p.Gln51_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.144_158del	p.Gln51_Gln55del	inframe_deletion	2/23	1	NM_002693.3	ENSP00000268124	P1
POLGARF	ENST00000706918.1	c.199_213del	p.Ala67_Ala71del	inframe_deletion	1/2			ENSP00000516626	P1

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 151604 Hom.: 0 Cov.: 30

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.: 0 AF XY: 0.000136 AC XY: 98 AN XY: 719198

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: 29 AN: 151708 Hom.: 0 Cov.: 30 AF XY: 0.000202 AC XY: 15 AN XY: 74160

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

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 06, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 02, 2014	The variant is found in INFANT-EPI,EPILEPSY,MITONUC-MITOP panel(s). -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 28, 2019

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

Likely 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;