9-32974495-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_001195248.2(APTX):c.837G>A(p.Trp279Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000369 in 1,608,946 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00037 ( 0 hom. )

Consequence

APTX
NM_001195248.2 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:17

Conservation

PhyloP100: 7.40

Variant links:

Genes affected

APTX (HGNC:15984): (aprataxin) This gene encodes a member of the histidine triad (HIT) superfamily. The encoded protein may play a role in single-stranded DNA repair through its nucleotide-binding activity and its diadenosine polyphosphate hydrolase activity. Mutations in this gene have been associated with ataxia-ocular apraxia. Alternatively spliced transcript variants have been identified for this gene.[provided by RefSeq, Aug 2010]

APTX links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 10 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 9-32974495-C-T is Pathogenic according to our data. Variant chr9-32974495-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 4431.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-32974495-C-T is described in Lovd as [Pathogenic]. Variant chr9-32974495-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APTX	NM_001195248.2 linkuse as main transcript	c.837G>A	p.Trp279Ter	stop_gained	7/8	ENST00000379817.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APTX	ENST00000379817.7 linkuse as main transcript	c.837G>A	p.Trp279Ter	stop_gained	7/8	1	NM_001195248.2	P1	Q7Z2E3-7

Frequencies

GnomAD3 genomes

AF:

0.000395

AC:

AN:

152038

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000852

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000618

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000155

AC:

AN:

250908

Hom.:

AF XY:

0.000133

AC XY:

AN XY:

135634

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000260

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:

0.000247

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000367

AC:

534

AN:

1456908

Hom.:

Cov.:

AF XY:

0.000339

AC XY:

246

AN XY:

725128

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000451

Gnomad4 OTH exome

AF:

0.000398

GnomAD4 genome

AF:

0.000395

AC:

AN:

152038

Hom.:

Cov.:

AF XY:

0.000350

AC XY:

AN XY:

74272

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.000852

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000618

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000375

Hom.:

Bravo

AF:

0.000378

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000107

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia

Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 08, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2011	- -
Pathogenic, criteria provided, single submitter	research	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	-	The pathogenic APTX c.837G>A (p.W279*) nonsense variant is predicted to result in nonsense-mediated decay or premature termination of the APTX protein. This variant has been reported in the homozygous or compound heterozygous state in multiple individuals with ataxia with oculomotor apraxia type 1 (PMID: 11586300; 14506070; 12629250; 15164193; 21465257). -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Jan 27, 2023	ACMG classification criteria: PVS1 strong, PM3 very strong, PP1 strong -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 27, 2016	The p.Trp279X variant in APTX has been reported in 15 families with ataxia-oculo motor apraxia 1. In 12 of the families, affected individuals carried the variant in a homozygous state (Moreira 2001, Barbot 2001, Tranchant 2003, Le Ber 2003), whereas in 2 of the families the patients were compound heterozygotes (Tranchan t 2003, Le Ber 2003). This variant has also been identified in 13/121,084 chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs104894103). Although this variant has been seen in the general populati on, its frequency is low enough to be consistent with a recessive carrier freque ncy. This nonsense variant leads to a premature termination codon at position 27 9, which is predicted to lead to a truncated or absent protein. Loss of function of the APTX gene is associated with ataxia-oculomotor apraxia 1. In summary, t his variant meets our criteria to be classified as pathogenic for ataxia-oculomo tor apraxia 1 in an autosomal recessive manner based upon biallelic case observa tions, low frequency in control populations and predicted loss of function impac t. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 08, 2017	The APTX c.837G>A (p.Trp279Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. Across a selection of the available literature, the p.Trp279Ter variant has been reported in 27 individuals with ataxia with oculomotor apraxia, type 1 (AOA1), including in 19 individuals from 17 families in a homozygous state, in seven individuals from five families in a compound heterozygous state, and in a heterozygous state in one individual in whom a second variant could not be identified (Moreira et al. 2001; Tranchant et al. 2003; Quinzii et al. 2005; Le Ber et al. 2007; Castellotti et al. 2011). The p.Trp279Ter variant was shown to co-segregate with the disease in one family and has been associated with a Portuguese founding haplotype. The variant causes the loss of approximately 19% of the aprataxin protein, including the zinc-finger domain that represents a putative DNA binding site, suggesting it may have a deleterious effect on the protein's proposed role in DNA repair. Control data are unavailable for this variant, which is reported at a frequency of 0.000349 in the European American population of the Exome Sequencing Project. Based on the collective evidence and the potential impact of stop-gained variants, the p.Trp279Ter variant is classified as pathogenic for ataxia with oculomotor apraxia, type 1. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, no assertion criteria provided	research	Section for Clinical Neurogenetics, University of Tübingen	Aug 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 23, 2015	- -

not provided

Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 26, 2022	Published functional studies demonstrate a damaging effect indicating that W279X is associated with no Aprataxin activity (Seidle et al., 2005); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 64 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 11294920, 16400613, 25989649, 15699391, 11586300, 12629250, 17242337, 21465257, 31493945, 29891053, 15790557, 32750061, 31589614, 30609409, 29482223, 32214227, 15996403, 29913018, 15800456, 32488064, 29356829, 16700949, 29915382, 25525159, 34426522, 15164193, 32769066, 32606550, 33101765) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 30, 2023	This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple individuals with clinical features associated with this gene. This variant segregates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. Study showed this variant produced protein with lower stability and lower enzymatic activity than wild type (PMID: 15790557). 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	Invitae	Nov 30, 2022	This variant is present in population databases (rs104894103, gnomAD 0.03%). This sequence change creates a premature translational stop signal (p.Trp279) in the APTX gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 64 amino acid(s) of the APTX protein. This premature translational stop signal has been observed in individuals with cerebellar ataxia with oculomotor apraxia (PMID: 11586300, 12629250, 14506070, 15996403, 16700949, 29356829, 29482223). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this premature translational stop signal affects APTX function (PMID: 15790557). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 4431). This variant is also known as c.879G>A; p.Trp293. -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 26, 2014	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 22, 2021

The c.837G>A (p.W279*) alteration, located in exon 8 (coding exon 6) of the APTX gene, consists of a G to A substitution at nucleotide position 837. This changes the amino acid from a tryptophan (W) to a stop codon at amino acid position 279. This alteration occurs at the 3' terminus of the APTX gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 18% of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein stability. Based on data from the Genome Aggregation Database (gnomAD) database, the APTX c.837G>A alteration was observed in 0.02% (51/282248) of total alleles studied, with a frequency of 0.03% (37/128976) in the European (non-Finnish) subpopulation. The c.837G>A (p.W279*) alteration has been reported in over 50 patients with ataxia-oculomotor apraxia either homozygous or compound heterozygous with a second pathogenic allele. This is the most common pathogenic allele in the European population (Le Ber, 2003; Mahajnah, 2005; Moreira, 2001; Renaud, 2018; Tranchant, 2003). Functional analysis demonstrated that the p.W279* alteration results in the absence of protein product in cells and significantly diminishes enzyme activity (Seidle, 2005; Shahwan, 2006). Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.65

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

0.99

MutationTaster

Benign

1.0

A;A;A;A;A;A;A;A;A;A

Vest4

0.89

GERP RS

6.0

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.18

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

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