15-89333627-TGCCGCCGCC-TGCCGCC

Position:

• chr15-89333627-TGCCGCCGCC-TGCCGCC

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6

The NM_002693.3(POLG):​c.125_127del​(p.Arg42del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000839 in 1,429,728 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in Lovd as Likely benign (no stars). Synonymous variant affecting the same amino acid position (i.e. R42R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000084 (0 hom.)
• Consequence: POLG NM_002693.3 inframe_deletion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.749

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 Likely_benign. Variant got -1 ACMG points.

• BP6: Variant 15-89333627-TGCC-T is Benign according to our data. Variant chr15-89333627-TGCC-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLG	NM_002693.3	c.125_127del	p.Arg42del	inframe_deletion	2/23	ENST00000268124.11
POLGARF	NM_001406557.1	c.180_182del	p.Ala71del	inframe_deletion	2/23
POLG	NM_001126131.2	c.125_127del	p.Arg42del	inframe_deletion	2/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLG	ENST00000268124.11	c.125_127del	p.Arg42del	inframe_deletion	2/23	1	NM_002693.3	P1
POLGARF	ENST00000706918.1	c.180_182del	p.Ala71del	inframe_deletion	1/2			P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000839 AC: 12 AN: 1429728 Hom.: 0 AF XY: 0.0000127 AC XY: 9 AN XY: 709868

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000241

Gnomad4 ASJ exome AF: 0.0000389

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000135

Gnomad4 NFE exome AF: 0.00000273

Gnomad4 OTH exome AF: 0.0000169

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs761080016; hg19: chr15-89876858;