X-25007238-AGGCGGCGGCGGC-AGGCGGCGGCGGCGGC

Variant names:

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP3BP6_Very_StrongBS1BS2

The NM_139058.3(ARX):c.1318_1320dupGCC(p.Ala440dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000493 in 1,126,838 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 152 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00055 ( 0 hom., 17 hem., cov: 23)

Exomes 𝑓: 0.00049 ( 0 hom. 135 hem. )

Consequence

ARX
NM_139058.3 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:7

Conservation

PhyloP100: 2.21

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -17 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_139058.3

BP6

Variant X-25007238-A-AGGC is Benign according to our data. Variant chrX-25007238-A-AGGC is described in ClinVar as [Likely_benign]. Clinvar id is 157743.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000549 (61/111075) while in subpopulation NFE AF= 0.000702 (37/52734). AF 95% confidence interval is 0.000523. There are 0 homozygotes in gnomad4. There are 17 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 17 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARX	NM_139058.3 link	c.1318_1320dupGCC	p.Ala440dup	conservative_inframe_insertion	Exon 4 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.1318_1320dupGCC	p.Ala440dup	conservative_inframe_insertion	Exon 4 of 5	1	NM_139058.3	ENSP00000368332.4		Q96QS3
ARX	ENST00000637993.1 link	c.-72_-70dupGCC		upstream_gene_variant		5		ENSP00000490122.1		A0A1B0GUI3

Frequencies

GnomAD3 genomes

AF:

0.000549

AC:

AN:

111036

Hom.:

Cov.:

AF XY:

0.000510

AC XY:

AN XY:

33352

show subpopulations

Gnomad AFR

AF:

0.000623

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000939

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000574

Gnomad SAS

AF:

0.000375

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000702

Gnomad OTH

AF:

0.000669

GnomAD3 exomes

AF:

0.000363

AC:

AN:

63404

Hom.:

AF XY:

0.000184

AC XY:

AN XY:

16306

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000266

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00161

Gnomad SAS exome

AF:

0.000125

Gnomad FIN exome

AF:

0.000173

Gnomad NFE exome

AF:

0.000343

Gnomad OTH exome

AF:

0.00112

GnomAD4 exome

AF:

0.000487

AC:

495

AN:

1015763

Hom.:

Cov.:

AF XY:

0.000416

AC XY:

135

AN XY:

324249

show subpopulations

Gnomad4 AFR exome

AF:

0.000317

Gnomad4 AMR exome

AF:

0.000180

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000628

Gnomad4 SAS exome

AF:

0.000312

Gnomad4 FIN exome

AF:

0.000331

Gnomad4 NFE exome

AF:

0.000529

Gnomad4 OTH exome

AF:

0.000327

GnomAD4 genome

AF:

0.000549

AC:

AN:

111075

Hom.:

Cov.:

AF XY:

0.000509

AC XY:

AN XY:

33401

show subpopulations

Gnomad4 AFR

AF:

0.000622

Gnomad4 AMR

AF:

0.0000938

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000576

Gnomad4 SAS

AF:

0.000376

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000702

Gnomad4 OTH

AF:

0.000661

Bravo

AF:

0.000669

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:4

Sep 30, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 06, 2014

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Benign:1

Mar 30, 2016

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Benign:1

Jun 15, 2018

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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. -

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

Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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