9-32973556-T-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001195248.2(APTX):c.971A>T(p.Gln324Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00199 in 1,614,116 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (4 hom.)
• Consequence: APTX NM_001195248.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:7
• Conservation: PhyloP100: 6.73

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013023466).
• BP6: Variant 9-32973556-T-A is Benign according to our data. Variant chr9-32973556-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 136416.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=1, Uncertain_significance=4}. Variant chr9-32973556-T-A is described in Lovd as [Likely_benign]. Variant chr9-32973556-T-A is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APTX	NM_001195248.2	c.971A>T	p.Gln324Leu	missense_variant	8/8	ENST00000379817.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APTX	ENST00000379817.7	c.971A>T	p.Gln324Leu	missense_variant	8/8	1	NM_001195248.2	P1

Frequencies

GnomAD3 genomes AF: 0.00118 AC: 179 AN: 152120 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00221

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00113 AC: 283 AN: 251214 Hom.: 0 AF XY: 0.00118 AC XY: 160 AN XY: 135752

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000693

Gnomad NFE exome AF: 0.00217

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00207 AC: 3031 AN: 1461878 Hom.: 4 Cov.: 32 AF XY: 0.00197 AC XY: 1433 AN XY: 727238

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000337

Gnomad4 NFE exome AF: 0.00263

Gnomad4 OTH exome AF: 0.000944

GnomAD4 genome AF: 0.00118 AC: 179 AN: 152238 Hom.: 1 Cov.: 32 AF XY: 0.00101 AC XY: 75 AN XY: 74432

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00221

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00148 Hom.: 0

Bravo AF: 0.00110

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00233 AC: 20

ExAC AF: 0.00102 AC: 124

EpiCase AF: 0.00256

EpiControl AF: 0.00219

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 16, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 11, 2024	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 30, 2021	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Coenzyme Q10 deficiency, Oculomotor Apraxia Type Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

APTX-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 17, 2020

This variant is classified as likely 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	-0.21	T
BayesDel_noAF	Uncertain	-0.070
Cadd	Uncertain	24
Dann	Uncertain	0.98
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.0021
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.59	T;T;T;.;T;.;.;T;T
M_CAP	Uncertain	0.093	D
MetaRNN	Benign	0.013	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.23	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.40	T
Sift4G	Benign	0.72	T;T;T;T;T;T;T;T;T
Polyphen		0.022, 0.0090, 0.0060	.;B;B;.;B;.;.;.;.
Vest4		0.36
MVP		0.99
MPC		0.077
ClinPred		0.024	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.38
gMVP		0.56

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: rs141493373; hg19: chr9-32973554;