15-89333627-TGCCGCCGCC-TGCCGCC

Variant names:

• chr15-89333627-TGCC-T
• rs761080016
• NM_002693.3:c.125_127delGGC

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_002693.3(POLG):​c.125_127delGGC​(p.Arg42del) variant causes a disruptive 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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 disruptive_inframe_deletion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.749
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLG	NM_002693.3	c.125_127delGGC	p.Arg42del	disruptive_inframe_deletion	Exon 2 of 23	ENST00000268124.11	NP_002684.1
POLG	NM_001126131.2	c.125_127delGGC	p.Arg42del	disruptive_inframe_deletion	Exon 2 of 23		NP_001119603.1
POLGARF	NM_001430120.1	c.180_182delGGC	p.Ala61del	disruptive_inframe_deletion	Exon 1 of 2		NP_001417049.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLG	ENST00000268124.11	c.125_127delGGC	p.Arg42del	disruptive_inframe_deletion	Exon 2 of 23	1	NM_002693.3	ENSP00000268124.5
POLGARF	ENST00000706918.1	c.180_182delGGC	p.Ala61del	disruptive_inframe_deletion	Exon 1 of 2			ENSP00000516626.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000742 AC: 15 AN: 202064 AF XY: 0.0000896

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000325

Gnomad ASJ exome AF: 0.000108

Gnomad EAS exome AF: 0.0000660

Gnomad FIN exome AF: 0.000413

Gnomad NFE exome AF: 0.0000341

Gnomad OTH exome AF: 0.000190

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32846

American (AMR) AF: 0.0000241 AC: 1 AN: 41444

Ashkenazi Jewish (ASJ) AF: 0.0000389 AC: 1 AN: 25706

East Asian (EAS) AF: 0.00 AC: 0 AN: 38304

South Asian (SAS) AF: 0.00 AC: 0 AN: 83970

European-Finnish (FIN) AF: 0.000135 AC: 6 AN: 44434

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5678

European-Non Finnish (NFE) AF: 0.00000273 AC: 3 AN: 1098074

Other (OTH) AF: 0.0000169 AC: 1 AN: 59272

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.75

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

Other links and lift over

dbSNP: rs761080016; hg19: chr15-89876858; COSMIC: COSV99174810; COSMIC: COSV99174810;