rs34778324

chr9-32987596-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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. 11/18 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.36

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]

ACMG classification

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. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APTX	NM_001195248.2	c.431C>A	p.Ser144Tyr	missense_variant	4/8	ENST00000379817.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APTX	ENST00000379817.7	c.431C>A	p.Ser144Tyr	missense_variant	4/8	1	NM_001195248.2	P1

Frequencies

GnomAD3 genomes AF: 0.00553 AC: 842 AN: 152212 Hom.: 7 Cov.: 32

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.: 9 AF XY: 0.00554 AC XY: 752 AN XY: 135852

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.: 49 Cov.: 32 AF XY: 0.00772 AC XY: 5617 AN XY: 727212

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.: 7 Cov.: 32 AF XY: 0.00491 AC XY: 366 AN XY: 74500

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.: 9

Bravo AF: 0.00591

TwinsUK AF: 0.00836 AC: 31

ALSPAC AF: 0.0109 AC: 42

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00779 AC: 67

ExAC AF: 0.00575 AC: 698

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00954

EpiControl AF: 0.00996

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 25, 2017	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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	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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Invitae	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, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 14, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 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	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	9.2
Dann	Benign	0.66
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.16	N
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	T
MutationAssessor	Benign	1.0	L;.;.;.;L;.;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.26	T
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	T
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

Other links and lift over

dbSNP: rs34778324; hg19: chr9-32987594;