rs34778324

Positions:

chr9-32987596-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001195248.2(APTX):c.431C>A(p.Ser144Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00774 in 1,614,140 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0055 ( 7 hom., cov: 32)

Exomes 𝑓: 0.0080 ( 49 hom. )

Consequence

APTX
NM_001195248.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 1.36

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:

APTX (HGNC:):

APTX links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0061478317).

BP6

Variant 9-32987596-G-T is Benign according to our data. Variant chr9-32987596-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 136414.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-32987596-G-T is described in Lovd as [Benign]. Variant chr9-32987596-G-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00553 (842/152330) while in subpopulation NFE AF= 0.00923 (628/68026). AF 95% confidence interval is 0.00863. There are 7 homozygotes in gnomad4. There are 366 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APTX	NM_001195248.2 linkuse as main transcript	c.431C>A	p.Ser144Tyr	missense_variant	4/8	ENST00000379817.7	NP_001182177.2	Q7Z2E3-7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APTX	ENST00000379817.7 linkuse as main transcript	c.431C>A	p.Ser144Tyr	missense_variant	4/8	1	NM_001195248.2	ENSP00000369145.2		Q7Z2E3-7

Frequencies

GnomAD3 genomes

AF:

0.00553

AC:

842

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00166

Gnomad AMI

AF:

0.0154

Gnomad AMR

AF:

0.00537

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00207

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00923

Gnomad OTH

AF:

0.00766

GnomAD3 exomes

AF:

0.00562

AC:

1412

AN:

251332

Hom.:

AF XY:

0.00554

AC XY:

752

AN XY:

135852

show subpopulations

Gnomad AFR exome

AF:

0.00117

Gnomad AMR exome

AF:

0.00431

Gnomad ASJ exome

AF:

0.00258

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00296

Gnomad NFE exome

AF:

0.00980

Gnomad OTH exome

AF:

0.00636

GnomAD4 exome

AF:

0.00797

AC:

11654

AN:

1461810

Hom.:

Cov.:

AF XY:

0.00772

AC XY:

5617

AN XY:

727212

show subpopulations

Gnomad4 AFR exome

AF:

0.000956

Gnomad4 AMR exome

AF:

0.00523

Gnomad4 ASJ exome

AF:

0.00253

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00291

Gnomad4 NFE exome

AF:

0.00966

Gnomad4 OTH exome

AF:

0.00666

GnomAD4 genome

AF:

0.00553

AC:

842

AN:

152330

Hom.:

Cov.:

AF XY:

0.00491

AC XY:

366

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.00166

Gnomad4 AMR

AF:

0.00536

Gnomad4 ASJ

AF:

0.00259

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00207

Gnomad4 NFE

AF:

0.00923

Gnomad4 OTH

AF:

0.00758

Alfa

AF:

0.00807

Hom.:

Bravo

AF:

0.00591

TwinsUK

AF:

0.00836

AC:

ALSPAC

AF:

0.0109

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.00779

AC:

ExAC

AF:

0.00575

AC:

698

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00954

EpiControl

AF:

0.00996

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2014	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 02, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	May 09, 2017	BS1,BS2,BP6; This alteration has an allele frequency that is greater than expected for the associated disease, was seen in a healthy adult where full penetrance of the disorder is expected at an early age, and was reported as a benign/likely benign alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory). -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 25, 2017	- -

not provided

Benign:5

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 01, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	APTX: BS2 -

Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.27

CADD

Benign

9.2

DANN

Benign

0.66

DEOGEN2

Benign

0.15

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

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.60

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

MetaRNN

Benign

0.0061

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

MetaSVM

Benign

-0.41

MutationAssessor

Benign

1.0

L;.;.;.;L;.;.;.;.;.;.

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.3

N;N;.;N;N;N;N;N;.;N;N

REVEL

Uncertain

0.32

Sift

Benign

0.045

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

Sift4G

Benign

0.12

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

Polyphen

0.095, 0.33, 0.046

.;.;B;.;B;.;.;.;.;B;.

Vest4

0.23

MVP

0.68

MPC

0.095

ClinPred

0.0020

GERP RS

-0.18

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.10

gMVP

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

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