chr15-89333596-T-TTGCTGC

Variant names:

• chr15-89333596-T-TTGCTGC
• rs41550117
• NM_001430120.1:c.208_213dupGCAGCA

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 2P and 17B. PM1 BP3 BP6_Very_Strong BA1

The NM_001430120.1(POLGARF):​c.208_213dupGCAGCA​(p.Ala70_Ala71dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0296 in 1,598,052 control chromosomes in the GnomAD database, including 545 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A71A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.039 (173 hom., cov: 30)
  • Exomes 𝑓: 0.029 (372 hom.)
• Consequence: POLGARF NM_001430120.1 conservative_inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -2.20
• Publications: 13 publications found

Genes affected

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]

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]

POLG Gene-Disease associations (from GenCC):

• progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• mitochondrial DNA depletion syndrome 4a

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Ambry Genetics
• sensory ataxic neuropathy, dysarthria, and ophthalmoparesis

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, G2P
• autosomal dominant progressive external ophthalmoplegia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive progressive external ophthalmoplegia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial neurogastrointestinal encephalomyopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• recessive mitochondrial ataxia syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• spinocerebellar ataxia with epilepsy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 12 benign, 11 uncertain in NM_001430120.1
• BP3: Nonframeshift variant in repetitive region in NM_001430120.1
• BP6: Variant 15-89333596-T-TTGCTGC is Benign according to our data. Variant chr15-89333596-T-TTGCTGC is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 206484.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0739 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001430120.1. 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
	POLGARF	NM_001430120.1	MANE Select	c.208_213dupGCAGCA	p.Ala70_Ala71dup	conservative_inframe_insertion	Exon 1 of 2	NP_001417049.1	A0A3B3IS91
	POLG	NM_002693.3	MANE Select	c.153_158dupGCAGCA	p.Gln52_Gln53dup	disruptive_inframe_insertion	Exon 2 of 23	NP_002684.1	P54098
	POLG	NM_001126131.2		c.153_158dupGCAGCA	p.Gln52_Gln53dup	disruptive_inframe_insertion	Exon 2 of 23	NP_001119603.1	P54098

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLGARF	ENST00000706918.1	MANE Select	c.208_213dupGCAGCA	p.Ala70_Ala71dup	conservative_inframe_insertion	Exon 1 of 2	ENSP00000516626.1	A0A3B3IS91
	POLG	ENST00000268124.11	TSL:1 MANE Select	c.153_158dupGCAGCA	p.Gln52_Gln53dup	disruptive_inframe_insertion	Exon 2 of 23	ENSP00000268124.5	P54098
	POLG	ENST00000442287.6	TSL:1	c.153_158dupGCAGCA	p.Gln52_Gln53dup	disruptive_inframe_insertion	Exon 2 of 23	ENSP00000399851.2	P54098

Frequencies

GnomAD3 genomes AF: 0.0394 AC: 5975 AN: 151578 Hom.: 173 Cov.: 30

Gnomad AFR AF: 0.0763

Gnomad AMI AF: 0.00773

Gnomad AMR AF: 0.0322

Gnomad ASJ AF: 0.00779

Gnomad EAS AF: 0.00155

Gnomad SAS AF: 0.0112

Gnomad FIN AF: 0.0131

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0298

Gnomad OTH AF: 0.0385

GnomAD4 exome AF: 0.0286 AC: 41298 AN: 1446370 Hom.: 372 Cov.: 31 AF XY: 0.0278 AC XY: 19979 AN XY: 719178

African (AFR) AF: 0.0738 AC: 2423 AN: 32848

American (AMR) AF: 0.0173 AC: 759 AN: 43886

Ashkenazi Jewish (ASJ) AF: 0.00851 AC: 220 AN: 25858

East Asian (EAS) AF: 0.00104 AC: 41 AN: 39412

South Asian (SAS) AF: 0.0144 AC: 1232 AN: 85290

European-Finnish (FIN) AF: 0.0118 AC: 566 AN: 48036

Middle Eastern (MID) AF: 0.0207 AC: 118 AN: 5692

European-Non Finnish (NFE) AF: 0.0310 AC: 34258 AN: 1105648

Other (OTH) AF: 0.0282 AC: 1681 AN: 59700

GnomAD4 genome AF: 0.0394 AC: 5974 AN: 151682 Hom.: 173 Cov.: 30 AF XY: 0.0381 AC XY: 2826 AN XY: 74144

African (AFR) AF: 0.0761 AC: 3143 AN: 41290

American (AMR) AF: 0.0322 AC: 492 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00779 AC: 27 AN: 3466

East Asian (EAS) AF: 0.00155 AC: 8 AN: 5164

South Asian (SAS) AF: 0.0113 AC: 54 AN: 4796

European-Finnish (FIN) AF: 0.0131 AC: 138 AN: 10558

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0298 AC: 2019 AN: 67836

Other (OTH) AF: 0.0382 AC: 80 AN: 2096

Alfa AF: 0.0127 Hom.: 29

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	Autosomal recessive progressive external ophthalmoplegia (1)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Progressive sclerosing poliodystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-2.2
Mutation Taster		=86/14	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs41550117; hg19: chr15-89876827; COSMIC: COSV104571447; COSMIC: COSV104571447;