X-25007238-AGGCGGCGGCGGC-AGGCGGCGGC

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP3 BP6 BS1 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).

• 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

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]

ACMG classification

Verdict is Benign. Variant got -10 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 id is 410779.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}. Variant chrX-25007238-AGGC-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000163 (165/1011308) while in subpopulation AMR AF= 0.00147 (32/21798). AF 95% confidence interval is 0.00107. There are 0 homozygotes in gnomad4_exome. There are 11 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAdExome4 at 11 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 AF XY: 0.0000300 AC XY: 1 AN XY: 33347

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

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

Gnomad4 AFR exome AF: 0.000592

Gnomad4 AMR exome AF: 0.00147

Gnomad4 ASJ exome AF: 0.000179

Gnomad4 EAS exome AF: 0.000434

Gnomad4 SAS exome AF: 0.000225

Gnomad4 FIN exome AF: 0.000399

Gnomad4 NFE exome AF: 0.0000907

Gnomad4 OTH exome AF: 0.000258

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

Gnomad4 AFR AF: 0.0000327

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000288

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000759

Gnomad4 OTH AF: 0.00

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

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. -

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 -

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

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: rs398124508; hg19: chrX-25025355;