rs769735492

Variant names:

• chr15-89333588-GGCTGCTGTT-G
• rs769735492
• NM_002693.3:c.158_166delAACAGCAGC

Your query was ambiguous. Multiple possible variants found:

• chr15-89333588-GGCTGCTGTT-G
• chr15-89333588-GGCTGCTGTT-GGCTGCTGTTGCTGCTGTT

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_002693.3(POLG):​c.158_166delAACAGCAGC​(p.Gln53_Gln55del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000106 in 1,604,760 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Q53Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: POLG NM_002693.3 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 2.58
• 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: Likely_benign. The variant received -1 ACMG points.

• BP6: Variant 15-89333588-GGCTGCTGTT-G is Benign according to our data. Variant chr15-89333588-GGCTGCTGTT-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 501355.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002693.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLG	NM_002693.3	MANE Select	c.158_166delAACAGCAGC	p.Gln53_Gln55del	disruptive_inframe_deletion	Exon 2 of 23	NP_002684.1
	POLGARF	NM_001430120.1	MANE Select	c.213_221delAACAGCAGC	p.Thr72_Ala74del	disruptive_inframe_deletion	Exon 1 of 2	NP_001417049.1
	POLG	NM_001126131.2		c.158_166delAACAGCAGC	p.Gln53_Gln55del	disruptive_inframe_deletion	Exon 2 of 23	NP_001119603.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLG	ENST00000268124.11	TSL:1 MANE Select	c.158_166delAACAGCAGC	p.Gln53_Gln55del	disruptive_inframe_deletion	Exon 2 of 23	ENSP00000268124.5
	POLGARF	ENST00000706918.1	MANE Select	c.213_221delAACAGCAGC	p.Thr72_Ala74del	disruptive_inframe_deletion	Exon 1 of 2	ENSP00000516626.1
	POLG	ENST00000442287.6	TSL:1	c.158_166delAACAGCAGC	p.Gln53_Gln55del	disruptive_inframe_deletion	Exon 2 of 23	ENSP00000399851.2

Frequencies

GnomAD3 genomes AF: 0.0000530 AC: 8 AN: 150930 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000246

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000658

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000738

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000671 AC: 16 AN: 238304 AF XY: 0.0000765

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000102

Gnomad EAS exome AF: 0.000113

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000111 AC: 162 AN: 1453830 Hom.: 0 AF XY: 0.000113 AC XY: 82 AN XY: 723486

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

African (AFR) AF: 0.0000303 AC: 1 AN: 33038

American (AMR) AF: 0.00 AC: 0 AN: 44464

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26032

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39642

South Asian (SAS) AF: 0.00 AC: 0 AN: 86010

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50028

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.000133 AC: 147 AN: 1108842

Other (OTH) AF: 0.000150 AC: 9 AN: 60024

⚠️ 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 AF: 0.0000530 AC: 8 AN: 150930 Hom.: 0 Cov.: 30 AF XY: 0.0000407 AC XY: 3 AN XY: 73722

African (AFR) AF: 0.0000246 AC: 1 AN: 40584

American (AMR) AF: 0.0000658 AC: 1 AN: 15198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.000192 AC: 1 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000738 AC: 5 AN: 67788

Other (OTH) AF: 0.00 AC: 0 AN: 2076

Alfa AF: 0.0000480 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)
-	-	1	Progressive sclerosing poliodystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.6
Mutation Taster		=157/43	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs769735492; hg19: chr15-89876819;