rs746120093

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The NM_139058.3(ARX):c.1561G>A(p.Ala521Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000188 in 1,171,641 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 25)

Exomes 𝑓: 0.000019 ( 0 hom. 6 hem. )

Consequence

ARX
NM_139058.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 2.13

Variant links:

Genes affected

ARX (HGNC:18060): (aristaless related homeobox) This gene is a homeobox-containing gene expressed during development. The expressed protein contains two conserved domains, a C-peptide (or aristaless domain) and the prd-like class homeobox domain. It is a member of the group-II aristaless-related protein family whose members are expressed primarily in the central and/or peripheral nervous system. This gene is thought to be involved in CNS development. Expansion of a polyalanine tract and other mutations in this gene cause X-linked cognitive disability and epilepsy. [provided by RefSeq, Jul 2016]

ARX links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.859

BS2

High Hemizygotes in GnomAdExome4 at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARX	NM_139058.3 link	c.1561G>A	p.Ala521Thr	missense_variant	Exon 5 of 5	ENST00000379044.5	NP_620689.1	Q96QS3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARX	ENST00000379044.5 link	c.1561G>A	p.Ala521Thr	missense_variant	Exon 5 of 5	1	NM_139058.3	ENSP00000368332.4		Q96QS3
ARX	ENST00000636885.1 link	n.*62G>A		downstream_gene_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0000176

AC:

AN:

113455

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

35605

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000375

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000270

AC:

AN:

111006

Hom.:

AF XY:

0.0000277

AC XY:

AN XY:

36074

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000725

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000189

AC:

AN:

1058186

Hom.:

Cov.:

AF XY:

0.0000175

AC XY:

AN XY:

343164

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000231

Gnomad4 OTH exome

AF:

0.0000225

GnomAD4 genome

AF:

0.0000176

AC:

AN:

113455

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

35605

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000375

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000680

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.00000999

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 30, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ARX c.1561G>A (p.Ala521Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.7e-05 in 111006 control chromosomes, including one hemizygote. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1561G>A has been reported in the literature in an individual affected with X-linked lissencephaly with abnormal genitalia and cerebellar hypoplasia (Kato_2004). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 14722918). ClinVar contains an entry for this variant (Variation ID: 210322). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Inborn genetic diseases

Uncertain:1

Jun 06, 2016

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Intellectual disability, X-linked, with or without seizures, ARX-related;C3463992:Developmental and epileptic encephalopathy, 1

Uncertain:1

Sep 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 521 of the ARX protein (p.Ala521Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with ARX-related conditions (PMID: 14722918; internal data). ClinVar contains an entry for this variant (Variation ID: 210322). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ARX protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Intellectual disability

Uncertain:1

Dec 01, 2018

Diagnostic Laboratory, Strasbourg University Hospital

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.78

M_CAP

Pathogenic

0.90

MetaRNN

Pathogenic

0.86

MetaSVM

Benign

-0.30

MutationAssessor

Benign

0.55

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-1.6

REVEL

Uncertain

0.56

Sift

Benign

0.29

Sift4G

Uncertain

0.028

Polyphen

0.23

Vest4

0.66

MutPred

0.76

Gain of glycosylation at A521 (P = 0.0012);

MVP

0.99

MPC

1.7

ClinPred

0.20

GERP RS

4.1

Varity_R

0.22

gMVP

0.41

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