chrX-25007238-AGGC-A

Variant names:

• chrX-25007238-AGGC-A
• rs398124508
• NM_139058.3:c.1318_1320delGCC

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP3 BP6 BS2

The NM_139058.3(ARX):​c.1318_1320delGCC​(p.Ala440del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000152 in 1,122,372 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 12 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A440A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000054 (0 hom., 1 hem., cov: 22)
  • Exomes 𝑓: 0.00016 (0 hom. 11 hem.)
• Consequence: ARX NM_139058.3 conservative_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 2.71
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• genetic developmental and epileptic encephalopathy

  Inheritance: XL, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• intellectual disability, X-linked, with or without seizures, ARX-related

  Inheritance: XL Classification: DEFINITIVE, MODERATE Submitted by: Ambry Genetics, G2P
• Partington syndrome

  Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• X-linked complex neurodevelopmental disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• X-linked lissencephaly with abnormal genitalia

  Inheritance: XL Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
• infantile spasms

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• corpus callosum agenesis-abnormal genitalia syndrome

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• infantile epileptic-dyskinetic encephalopathy

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• X-linked spasticity-intellectual disability-epilepsy syndrome

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_139058.3
• BP6: Variant X-25007238-AGGC-A is Benign according to our data. Variant chrX-25007238-AGGC-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 410779.
• BS2: High AC in GnomAd4 at 6 AD,XL gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARX	NM_139058.3	c.1318_1320delGCC	p.Ala440del	conservative_inframe_deletion	Exon 4 of 5	ENST00000379044.5	NP_620689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARX	ENST00000379044.5	c.1318_1320delGCC	p.Ala440del	conservative_inframe_deletion	Exon 4 of 5	1	NM_139058.3	ENSP00000368332.4
ARX	ENST00000637993.1	c.-72_-70delGCC		upstream_gene_variant		5		ENSP00000490122.1

Frequencies

GnomAD3 genomes AF: 0.0000540 AC: 6 AN: 111025 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000328

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000287

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000758

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00150 AC: 95 AN: 63404 AF XY: 0.00

Gnomad AFR exome AF: 0.00420

Gnomad AMR exome AF: 0.00231

Gnomad ASJ exome AF: 0.00158

Gnomad EAS exome AF: 0.00207

Gnomad FIN exome AF: 0.00121

Gnomad NFE exome AF: 0.00103

Gnomad OTH exome AF: 0.00280

GnomAD4 exome AF: 0.000163 AC: 165 AN: 1011308 Hom.: 0 AF XY: 0.0000342 AC XY: 11 AN XY: 321776

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000592 AC: 13 AN: 21966

American (AMR) AF: 0.00147 AC: 32 AN: 21798

Ashkenazi Jewish (ASJ) AF: 0.000179 AC: 3 AN: 16787

East Asian (EAS) AF: 0.000434 AC: 11 AN: 25373

South Asian (SAS) AF: 0.000225 AC: 10 AN: 44449

European-Finnish (FIN) AF: 0.000399 AC: 12 AN: 30087

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3706

European-Non Finnish (NFE) AF: 0.0000907 AC: 73 AN: 804560

Other (OTH) AF: 0.000258 AC: 11 AN: 42582

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000540 AC: 6 AN: 111064 Hom.: 0 Cov.: 22 AF XY: 0.0000299 AC XY: 1 AN XY: 33396

African (AFR) AF: 0.0000327 AC: 1 AN: 30554

American (AMR) AF: 0.00 AC: 0 AN: 10663

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2635

East Asian (EAS) AF: 0.000288 AC: 1 AN: 3473

South Asian (SAS) AF: 0.00 AC: 0 AN: 2657

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5951

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 214

European-Non Finnish (NFE) AF: 0.0000759 AC: 4 AN: 52730

Other (OTH) AF: 0.00 AC: 0 AN: 1513

Alfa AF: 0.00173 Hom.: 1

Bravo AF: 0.0000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Intellectual disability, X-linked, with or without seizures, ARX-related Uncertain:1 Benign:1

Apr 25, 2023

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence variant is an in-frame deletion of 3 nucleotides at coding positions 1318 through 1320 of the ARX gene which removes the alanine amino acid at residue 440 of the ARX protein. This variant has not been reported in clinical genetics databases or observed in the medical literature in individuals with ARX-related disease, to our knowledge. This variant is present in 95/84504 alleles (0.1124%) in the gnomAD population database; it is notably only present in heterozygous females. This variant occurs in the last of four polyalanine domains in ARX. At this time, there is insufficient evidence to determine if this variant is pathogenic or benign. Therefore, we consider it to be a variant of uncertain significance. ACMG Criteria: BP3 -

Mar 30, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Likely benign. The following ACMG criteria were applied in classifying this variant: BS1,BP3. -

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

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.1318_1320del, results in the deletion of 1 amino acid(s) of the ARX protein (p.Ala440del), but otherwise preserves the integrity of the reading frame. 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 variant has not been reported in the literature in individuals affected with ARX-related conditions. ClinVar contains an entry for this variant (Variation ID: 410779). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

Inborn genetic diseases Benign:1

Jun 06, 2016

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

ARX-related disorder Benign:1

Apr 06, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
PhyloP100		2.7
Mutation Taster		=65/35	polymorphism

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

Other links and lift over

dbSNP: rs398124508; hg19: chrX-25025355;