rs758130

Positions:

• chr15-89330566-A-G
• chr15-89330566-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000268124.11(POLG):​c.660-290T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.366 in 152,024 control chromosomes in the GnomAD database, including 10,490 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.37 (10490 hom., cov: 32)
• Consequence: POLG ENST00000268124.11 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.96

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

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 15-89330566-A-G is Benign according to our data. Variant chr15-89330566-A-G is described in ClinVar as [Benign]. Clinvar id is 680713.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.394 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLG	NM_002693.3	c.660-290T>C		intron_variant		ENST00000268124.11	NP_002684.1
POLGARF	NM_001406557.1	c.715-290T>C		intron_variant			NP_001393486.1
POLG	NM_001126131.2	c.660-290T>C		intron_variant			NP_001119603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLG	ENST00000268124.11	c.660-290T>C		intron_variant		1	NM_002693.3	ENSP00000268124	P1
POLGARF	ENST00000706918.1	c.715-290T>C		intron_variant				ENSP00000516626	P1

Frequencies

GnomAD3 genomes AF: 0.366 AC: 55661 AN: 151906 Hom.: 10489 Cov.: 32

Gnomad AFR AF: 0.288

Gnomad AMI AF: 0.389

Gnomad AMR AF: 0.358

Gnomad ASJ AF: 0.375

Gnomad EAS AF: 0.323

Gnomad SAS AF: 0.391

Gnomad FIN AF: 0.490

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.398

Gnomad OTH AF: 0.362

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.366 AC: 55669 AN: 152024 Hom.: 10490 Cov.: 32 AF XY: 0.373 AC XY: 27721 AN XY: 74298

Gnomad4 AFR AF: 0.287

Gnomad4 AMR AF: 0.357

Gnomad4 ASJ AF: 0.375

Gnomad4 EAS AF: 0.323

Gnomad4 SAS AF: 0.392

Gnomad4 FIN AF: 0.490

Gnomad4 NFE AF: 0.398

Gnomad4 OTH AF: 0.359

Alfa AF: 0.382 Hom.: 11479

Bravo AF: 0.356

Asia WGS AF: 0.340 AC: 1180 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.029
DANN	Benign	0.27

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

Publications

LitVar

Other links and lift over

dbSNP: rs758130; hg19: chr15-89873797;