rs150886026

Positions:

chr9-32984805-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_001195248.2(APTX):c.596G>A(p.Arg199His) variant causes a missense change. The variant allele was found at a frequency of 0.0011 in 1,614,150 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R199C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0055 ( 10 hom., cov: 32)

Exomes 𝑓: 0.00064 ( 9 hom. )

Consequence

APTX
NM_001195248.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 6.16

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 Benign. Variant got -18 ACMG points.

PM1

In a domain HIT (size 105) in uniprot entity APTX_HUMAN there are 31 pathogenic changes around while only 5 benign (86%) in NM_001195248.2

BP4

Computational evidence support a benign effect (MetaRNN=0.012209952).

BP6

Variant 9-32984805-C-T is Benign according to our data. Variant chr9-32984805-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 214120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-32984805-C-T is described in Lovd as [Pathogenic]. Variant chr9-32984805-C-T is described in Lovd as [Pathogenic].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00547 (833/152274) while in subpopulation AFR AF= 0.0188 (780/41546). AF 95% confidence interval is 0.0177. There are 10 homozygotes in gnomad4. There are 389 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APTX	NM_001195248.2 linkuse as main transcript	c.596G>A	p.Arg199His	missense_variant	6/8	ENST00000379817.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APTX	ENST00000379817.7 linkuse as main transcript	c.596G>A	p.Arg199His	missense_variant	6/8	1	NM_001195248.2	P1	Q7Z2E3-7

Frequencies

GnomAD3 genomes

AF:

0.00547

AC:

832

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0188

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00242

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00430

GnomAD3 exomes

AF:

0.00163

AC:

410

AN:

251468

Hom.:

AF XY:

0.00136

AC XY:

185

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.0195

Gnomad AMR exome

AF:

0.00107

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00150

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000527

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000642

AC:

939

AN:

1461876

Hom.:

Cov.:

AF XY:

0.000626

AC XY:

455

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.0196

Gnomad4 AMR exome

AF:

0.00127

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00118

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000306

Gnomad4 OTH exome

AF:

0.00132

GnomAD4 genome

AF:

0.00547

AC:

833

AN:

152274

Hom.:

Cov.:

AF XY:

0.00522

AC XY:

389

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.0188

Gnomad4 AMR

AF:

0.00242

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00426

Alfa

AF:

0.000949

Hom.:

Bravo

AF:

0.00627

ESP6500AA

AF:

0.0182

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00207

AC:

251

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	APTX: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 13, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 22, 2017	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 01, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 18, 2020	- -

Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

APTX-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 22, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

0.0

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.72

.;.;.;.;.;D;.;.;.;.;D;D;D

Eigen

Uncertain

0.23

Eigen_PC

Benign

0.21

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

D;D;D;D;.;D;.;.;D;D;D;D;D

MetaRNN

Benign

0.012

T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.51

MutationAssessor

Uncertain

2.2

M;.;.;.;.;M;.;.;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-3.2

D;.;.;D;D;D;D;D;D;.;D;D;D

REVEL

Uncertain

0.59

Sift

Benign

0.061

T;.;.;D;D;D;D;D;D;.;D;T;T

Sift4G

Benign

0.073

T;T;T;T;T;T;T;T;T;T;.;.;.

Polyphen

0.77, 0.86, 0.63, 0.99

.;.;P;P;.;P;.;.;.;.;.;D;.

Vest4

0.86

MVP

0.97

MPC

0.28

ClinPred

0.021

GERP RS

4.0

Varity_R

0.40

gMVP

0.60

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

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