9-32984659-A-T

Position:

chr9-32984659-A-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_001195248.2(APTX):c.742T>A(p.Leu248Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00177 in 1,614,180 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0018 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 5 hom. )

Consequence

APTX
NM_001195248.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:4

Conservation

PhyloP100: -1.02

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 -11 ACMG points.

PM1

In a domain HIT (size 105) in uniprot entity APTX_HUMAN there are 24 pathogenic changes around while only 2 benign (92%) in NM_001195248.2

BP4

Computational evidence support a benign effect (MetaRNN=0.01604551).

BP6

Variant 9-32984659-A-T is Benign according to our data. Variant chr9-32984659-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 214122.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=5}.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00178 (271/152290) while in subpopulation AMR AF= 0.00405 (62/15294). AF 95% confidence interval is 0.00325. There are 1 homozygotes in gnomad4. There are 126 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APTX	NM_001195248.2 linkuse as main transcript	c.742T>A	p.Leu248Met	missense_variant	6/8	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.742T>A	p.Leu248Met	missense_variant	6/8	1	NM_001195248.2	ENSP00000369145.2		Q7Z2E3-7

Frequencies

GnomAD3 genomes

AF:

0.00179

AC:

272

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000628

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00406

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00243

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00135

AC:

339

AN:

251318

Hom.:

AF XY:

0.00138

AC XY:

188

AN XY:

135826

show subpopulations

Gnomad AFR exome

AF:

0.000615

Gnomad AMR exome

AF:

0.00130

Gnomad ASJ exome

AF:

0.00149

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000231

Gnomad NFE exome

AF:

0.00224

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00177

AC:

2593

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00177

AC XY:

1285

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.000687

Gnomad4 AMR exome

AF:

0.00165

Gnomad4 ASJ exome

AF:

0.00138

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.000300

Gnomad4 NFE exome

AF:

0.00210

Gnomad4 OTH exome

AF:

0.00157

GnomAD4 genome

AF:

0.00178

AC:

271

AN:

152290

Hom.:

Cov.:

AF XY:

0.00169

AC XY:

126

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.000626

Gnomad4 AMR

AF:

0.00405

Gnomad4 ASJ

AF:

0.00346

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00241

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00209

Hom.:

Bravo

AF:

0.00172

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00233

AC:

ExAC

AF:

0.00138

AC:

168

EpiCase

AF:

0.00262

EpiControl

AF:

0.00279

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 13, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	APTX: BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 22, 2024	Observed in in individuals with ataxia in published literature; however, a second APTX variant was not detected and L248M was identified in unaffected family members (PMID: 21465257); Published functional studies indicate that although this variant has a stabilizing effect it impairs active site assembly (PMID: 29934293); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25637650, 26285866, 28881617, 29934293, 21465257) -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -

Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 04, 2023	The APTX c.742T>A; p.Leu248Met variant (rs141195622), is reported in the literature in at least one individual affected with ataxia with oculomotor apraxia type 1 (van Minkelen 2015). This variant is reported in ClinVar (Variation ID: 214122), and is found in the general population with an overall allele frequency of 0.13% (373/277,044 alleles) in the Genome Aggregation Database. The leucine at codon 248 is moderately conserved, and computational analyses (SIFT: tolerated, PolyPhen-2: possibly damaging) predict conflicting effects of this variant on protein structure/function. Due to limited information, the clinical significance of the p.Leu248Met variant is uncertain at this time. Pathogenic variants in the APTX gene are inherited in an autosomal recessive manner and are associated with early-onset ataxia with oculomotor apraxia and hypoalbuminemia (MIM: 208920). References: van Minkelen R et al. Complete APTX deletion in a patient with ataxia with oculomotor apraxia type 1. BMC Med Genet. 2015 Aug 19;16:61. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 20, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. These variants have been previously reported but pathogenicity of these changes is unclear [PMID 26285866] -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 16, 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jul 31, 2024

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 17, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.17

CADD

Benign

8.6

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.59

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

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.096

LIST_S2

Benign

0.78

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

M_CAP

Benign

0.073

MetaRNN

Benign

0.016

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

MetaSVM

Uncertain

0.077

MutationAssessor

Benign

0.85

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

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.85

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

REVEL

Uncertain

0.40

Sift

Benign

0.049

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

Sift4G

Benign

0.18

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

Polyphen

0.86, 0.24, 0.89, 0.89

.;.;P;B;.;P;.;.;.;.;.;P

Vest4

0.34

MVP

0.62

MPC

0.10

ClinPred

0.029

GERP RS

-7.1

Varity_R

0.23

gMVP

0.51

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