rs144439703

Variant names:

• chr15-89333491-G-A
• rs144439703
• NM_001430120.1:c.319C>T
• POLGARF p.Arg107Trp

Your query was ambiguous. Multiple possible variants found:

• chr15-89333491-G-A
• chr15-89333491-G-C

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM5 BP4_Strong BP6 BS2

The NM_001430120.1(POLGARF):​c.319C>T​(p.Arg107Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00181 in 1,612,662 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R107G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 34)
  • Exomes 𝑓: 0.0019 (11 hom.)
• Consequence: POLGARF NM_001430120.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:17
• Conservation: PhyloP100: 2.24
• Publications: 6 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• mitochondrial DNA depletion syndrome 4a

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

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P, Ambry Genetics
• 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 -7 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-89333491-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 381522.
• BP4: Computational evidence support a benign effect (MetaRNN=0.007884175).
• BP6: Variant 15-89333491-G-A is Benign according to our data. Variant chr15-89333491-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 129992.
• BS2: High Homozygotes in GnomAdExome4 at 11 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.319C>T	p.Arg107Trp	missense	Exon 1 of 2	NP_001417049.1	A0A3B3IS91
	POLG	NM_002693.3	MANE Select	c.264C>T	p.Phe88Phe	synonymous	Exon 2 of 23	NP_002684.1	P54098
	POLG	NM_001126131.2		c.264C>T	p.Phe88Phe	synonymous	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.319C>T	p.Arg107Trp	missense	Exon 1 of 2	ENSP00000516626.1	A0A3B3IS91
	POLG	ENST00000268124.11	TSL:1 MANE Select	c.264C>T	p.Phe88Phe	synonymous	Exon 2 of 23	ENSP00000268124.5	P54098
	POLG	ENST00000442287.6	TSL:1	c.264C>T	p.Phe88Phe	synonymous	Exon 2 of 23	ENSP00000399851.2	P54098

Frequencies

GnomAD3 genomes AF: 0.00128 AC: 195 AN: 152260 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000915

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00220

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.00177 AC: 440 AN: 248876 AF XY: 0.00204

Gnomad AFR exome AF: 0.000496

Gnomad AMR exome AF: 0.00124

Gnomad ASJ exome AF: 0.0000996

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000142

Gnomad NFE exome AF: 0.00244

Gnomad OTH exome AF: 0.00148

GnomAD4 exome AF: 0.00186 AC: 2721 AN: 1460284 Hom.: 11 Cov.: 32 AF XY: 0.00199 AC XY: 1449 AN XY: 726570

African (AFR) AF: 0.000329 AC: 11 AN: 33456

American (AMR) AF: 0.00112 AC: 50 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.0000766 AC: 2 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00355 AC: 306 AN: 86256

European-Finnish (FIN) AF: 0.000172 AC: 9 AN: 52296

Middle Eastern (MID) AF: 0.00780 AC: 45 AN: 5768

European-Non Finnish (NFE) AF: 0.00199 AC: 2209 AN: 1111664

Other (OTH) AF: 0.00147 AC: 89 AN: 60354

GnomAD4 genome AF: 0.00128 AC: 195 AN: 152378 Hom.: 1 Cov.: 34 AF XY: 0.00126 AC XY: 94 AN XY: 74520

African (AFR) AF: 0.000337 AC: 14 AN: 41596

American (AMR) AF: 0.000914 AC: 14 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4828

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00220 AC: 150 AN: 68036

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00119 Hom.: 0

Bravo AF: 0.00123

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00284

EpiControl AF: 0.00373

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	6	not provided (6)
-	-	2	Progressive sclerosing poliodystrophy (2)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Inborn genetic diseases (1)
-	1	-	POLG-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_noAF	Benign	-0.45
CADD	Pathogenic	26
DANN	Benign	0.95
FATHMM_MKL	Uncertain	0.87	D
MetaRNN	Benign	0.0079	T
PhyloP100		2.2
PromoterAI		-0.0042	Neutral
Mutation Taster		=100/0	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs144439703;

hg19: chr15-89876722;

COSMIC: COSV51524895;

COSMIC: COSV51524895;