rs778573169

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP5_Very_Strong

The ENST00000268124.11(POLG):c.3104+3A>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,614,058 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

POLG
ENST00000268124.11 splice_donor_region, intron

Scores

Splicing: ADA: 0.9995

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 0.518

Variant links:

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]

POLG links:

POLGARF (HGNC:):

POLGARF links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PP5

Variant 15-89319225-T-A is Pathogenic according to our data. Variant chr15-89319225-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 587863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein
POLG	NM_002693.3 linkuse as main transcript	c.3104+3A>T	splice_donor_region_variant, intron_variant	ENST00000268124.11	NP_002684.1
POLGARF	NM_001406557.1 linkuse as main transcript	c.*2376+3A>T	splice_donor_region_variant, intron_variant		NP_001393486.1
POLG	NM_001126131.2 linkuse as main transcript	c.3104+3A>T	splice_donor_region_variant, intron_variant		NP_001119603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLG	ENST00000268124.11 linkuse as main transcript	c.3104+3A>T		splice_donor_region_variant, intron_variant		1	NM_002693.3	ENSP00000268124	P1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000398

AC:

AN:

251462

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000185

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000207

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Progressive sclerosing poliodystrophy

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	Oct 01, 2018	The NM_002693.2:c.3104+3A>T (NP_002684.1:p.=) [GRCH38: NC_000015.10:g.89319225T>A] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:21670405 . This variant meets the following evidence codes reported in the ACMG-guideline. PS3:Well established functional studies show a deleterious effect on POLG. PM2:This variant is absent in key population databases. PM3:Detected in trans with a pathogenic variant for Mitochondrial DNA depletion syndrome 4A (Alpers type) which is a recessive disorder. PP1:This variant is co-segregated with Mitochondrial DNA depletion syndrome 4A (Alpers type) in multiple affected family members. PP4:Patient's phenotype or family history is highly specific for POLG. Based on the evidence criteria codes applied, the variant is suggested to be Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 18, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2022	For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of 19, but is expected to preserve the integrity of the reading-frame (PMID: 21670405). ClinVar contains an entry for this variant (Variation ID: 587863). This variant has been observed in individual(s) with progressive external ophthalmoplegia (PMID: 21670405). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs778573169, gnomAD 0.008%). This sequence change falls in intron 19 of the POLG gene. It does not directly change the encoded amino acid sequence of the POLG protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 30, 2022	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 23446635) In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 12, 2022	Non-canonical splice site variant demonstrated to result in loss of function (Milone M, 2011; Roos S, 2013); This variant is associated with the following publications: (PMID: 34777884, 25525159, 32153140, 21880868, 23446635, 21670405, 28480171) -

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

Feb 21, 2024

This sequence variant is a single nucleotide substitution (A>T) three bases past exon 19 of the POLG gene. This is a previously reported variant (ClinVar) that has been observed in the compound heterozygous state with a second pathogenic POLG variant. Affected individuals exhibited a variety of phenotypes including, but not limited to, progressive exterl ophthalmoplegia, ptosis, optic atrophy, hearing loss, muscle weakness, cognitive impairment, exercise intolerance, and mitochondrial myopathy (PMID: 34777884, 23446635, 21670405). This variant is present in 10 of 251,462 alleles in the gnomAD population database (0.004%). Multiple bioinformatic tools predict that A to T nucleotide change would impact R splicing resulting in the loss of the intron 19 donor splice site, however the A at this position is poorly conserved across the vertebrate species examined. R sequencing confirms that this variant disrupts proper splicing, removes exon 19 from the transcript, and causes the in-frame deletion of a portion of the POLG polymerase finger domain (PMID: 23446635, 21670405). Further alysis confirms that this altered splicing results in a shortened protein product that fails to replicate D and has negligible exonuclease activity (PMID: 23446635). Given this information, we consider this a pathogenic variant. ACMG Criteria: PM1, PM2, PM3, PS3 -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 09, 2018

The c.3104+3A>T intronic pathogenic mutation results from an A to T substitution 3 nucleotides after coding exon 18 in the POLG gene. This mutation results in in-frame skipping of coding exon 18, resulting in loss of 41 amino acids and a shortened product, though exon skipping is incomplete and some normal-length transcripts are also produced (Milone M et al. Arch. Neurol. 2011;68(6):806-11; Roos S et al. Hum. Mol. Genet. 2013;22(12):2411-22). This mutation was first described by Milone et al. in two unrelated individuals compound heterozygous for different POLG mutations, who had features of mitochondrial depletion syndrome diagnosed in their sixties, including scattered ragged-red and ragged-blue fibers and numerous cytochrome c oxidase-negative fibers on muscle biopsy, progressive external ophthalmoplegia (PEO), ptosis, and myopathy. The asymptomatic mother of one proband was found to be heterozygous for this mutation. Roos et al. described this mutation in two brothers with adult onset PEO, muscle pain, weakness, cognitive impairment, and consistently elevated creatine kinase levels, who were compound heterozygous for a missense POLG mutation. Analyses of DNA synthesis revealed that the shortened transcript was unable to support DNA synthesis. However, the mutant transcript did not interfere with wildtype (WT) POLG activity even when present at a higher molar ratio than the WT, demonstrating an autosomal recessive phenotype for this mutation with adult onset. As such, this alteration is classified as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Benign

0.76

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.90

SpliceAI score (max)

0.75

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.75

Position offset: 3

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over