NM_001430120.1:c.208_213delGCAGCA

Variant names:

• chr15-89333596-TTGCTGC-T
• rs41550117
• NM_001430120.1:c.208_213delGCAGCA

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1 BP3 BP6_Very_Strong BS2

The NM_001430120.1(POLGARF):​c.208_213delGCAGCA​(p.Ala70_Ala71del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00454 in 1,597,982 control chromosomes in the GnomAD database, including 23 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (2 hom., cov: 30)
  • Exomes 𝑓: 0.0046 (21 hom.)
• Consequence: POLGARF NM_001430120.1 conservative_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.0750
• 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 -11 ACMG points.

• PM1: In a hotspot region, there are 8 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-TTGCTGC-T is Benign according to our data. Variant chr15-89333596-TTGCTGC-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 167523.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 2 gene

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_213delGCAGCA	p.Ala70_Ala71del	conservative_inframe_deletion	Exon 1 of 2	NP_001417049.1	A0A3B3IS91
	POLG	NM_002693.3	MANE Select	c.153_158delGCAGCA	p.Gln52_Gln53del	disruptive_inframe_deletion	Exon 2 of 23	NP_002684.1	P54098
	POLG	NM_001126131.2		c.153_158delGCAGCA	p.Gln52_Gln53del	disruptive_inframe_deletion	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_213delGCAGCA	p.Ala70_Ala71del	conservative_inframe_deletion	Exon 1 of 2	ENSP00000516626.1	A0A3B3IS91
	POLG	ENST00000268124.11	TSL:1 MANE Select	c.153_158delGCAGCA	p.Gln52_Gln53del	disruptive_inframe_deletion	Exon 2 of 23	ENSP00000268124.5	P54098
	POLG	ENST00000442287.6	TSL:1	c.153_158delGCAGCA	p.Gln52_Gln53del	disruptive_inframe_deletion	Exon 2 of 23	ENSP00000399851.2	P54098

Frequencies

GnomAD3 genomes AF: 0.00402 AC: 610 AN: 151602 Hom.: 2 Cov.: 30

Gnomad AFR AF: 0.00158

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.00656

Gnomad ASJ AF: 0.00721

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00549

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00488

Gnomad OTH AF: 0.00723

GnomAD4 exome AF: 0.00459 AC: 6634 AN: 1446276 Hom.: 21 AF XY: 0.00452 AC XY: 3247 AN XY: 719132

African (AFR) AF: 0.00143 AC: 47 AN: 32852

American (AMR) AF: 0.00501 AC: 220 AN: 43876

Ashkenazi Jewish (ASJ) AF: 0.00743 AC: 192 AN: 25858

East Asian (EAS) AF: 0.000787 AC: 31 AN: 39412

South Asian (SAS) AF: 0.000879 AC: 75 AN: 85282

European-Finnish (FIN) AF: 0.00402 AC: 193 AN: 47994

Middle Eastern (MID) AF: 0.00369 AC: 21 AN: 5694

European-Non Finnish (NFE) AF: 0.00508 AC: 5621 AN: 1105614

Other (OTH) AF: 0.00392 AC: 234 AN: 59694

GnomAD4 genome AF: 0.00404 AC: 613 AN: 151706 Hom.: 2 Cov.: 30 AF XY: 0.00379 AC XY: 281 AN XY: 74158

African (AFR) AF: 0.00157 AC: 65 AN: 41308

American (AMR) AF: 0.00655 AC: 100 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00721 AC: 25 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4796

European-Finnish (FIN) AF: 0.00549 AC: 58 AN: 10558

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00488 AC: 331 AN: 67844

Other (OTH) AF: 0.00859 AC: 18 AN: 2096

Alfa AF: 0.00293 Hom.: 29

Bravo AF: 0.00445

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	not specified (3)
-	-	1	Inborn genetic diseases (1)
-	-	1	Progressive sclerosing poliodystrophy (1)
-	-	1	Progressive sclerosing poliodystrophy;C1834846:Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1;C1843851:Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis;C3150914:Mitochondrial DNA depletion syndrome 4b;C4225153:Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1;C4551995:Mitochondrial DNA depletion syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.075
Mutation Taster		=79/121	disease causing

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: COSV51521459; COSMIC: COSV51521459;