15-89333627-TGCCGCCGCC-TGCCGCCGCCGCCGCCGCC

Variant names:

• chr15-89333627-T-TGCCGCCGCC
• rs761080016
• NM_002693.3:c.119_127dupGGCGGCGGC

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_002693.3(POLG):​c.119_127dupGGCGGCGGC​(p.Arg40_Arg42dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. Q43Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: POLG NM_002693.3 conservative_inframe_insertion
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.749
• Publications: 0 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.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 15-89333627-T-TGCCGCCGCC is Benign according to our data. Variant chr15-89333627-T-TGCCGCCGCC is described in ClinVar as Likely_benign. ClinVar VariationId is 1744651.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLG	NM_002693.3	c.119_127dupGGCGGCGGC	p.Arg40_Arg42dup	conservative_inframe_insertion	Exon 2 of 23	ENST00000268124.11	NP_002684.1
POLG	NM_001126131.2	c.119_127dupGGCGGCGGC	p.Arg40_Arg42dup	conservative_inframe_insertion	Exon 2 of 23		NP_001119603.1
POLGARF	NM_001430120.1	c.174_182dupGGCGGCGGC	p.Ala59_Ala61dup	disruptive_inframe_insertion	Exon 1 of 2		NP_001417049.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLG	ENST00000268124.11	c.119_127dupGGCGGCGGC	p.Arg40_Arg42dup	conservative_inframe_insertion	Exon 2 of 23	1	NM_002693.3	ENSP00000268124.5
POLGARF	ENST00000706918.1	c.174_182dupGGCGGCGGC	p.Ala59_Ala61dup	disruptive_inframe_insertion	Exon 1 of 2			ENSP00000516626.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.99e-7 AC: 1 AN: 1429754 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 709888

⚠️ 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: 0.00 AC: 0 AN: 41446

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25708

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 83972

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44444

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

European-Non Finnish (NFE) AF: 9.11e-7 AC: 1 AN: 1098080

Other (OTH) AF: 0.00 AC: 0 AN: 59276

⚠️ 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

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Benign:1

Feb 25, 2020

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.75
Mutation Taster		=84/16	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs761080016; hg19: chr15-89876858;