X-25013659-TGCCGCCGCCGCCGCCGCCGCC-TGCCGCCGCCGCCGCCGCCGCCGCCGCC

Position:

• chrX-25013659-TGCCGCCGCCGCCGCCGCCGCC-TGCCGCCGCCGCCGCCGCCGCCGCCGCC

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP3 BP6 BS2

The ENST00000379044.5(ARX):​c.335_336insGGCGGC​(p.Ala114_Ala115dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000467 in 770,744 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 10 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. A112A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., 3 hem., cov: 22)
  • Exomes 𝑓: 0.000035 (0 hom. 7 hem.)
• Consequence: ARX ENST00000379044.5 inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 1.33

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 Likely_benign. Variant got -6 ACMG points.

• BP3: Nonframeshift variant in repetitive region in ENST00000379044.5
• BP6: Variant X-25013659-T-TGCCGCC is Benign according to our data. Variant chrX-25013659-T-TGCCGCC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 420027.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
• BS2: High Hemizygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARX	NM_139058.3	c.335_336insGGCGGC	p.Ala114_Ala115dup	inframe_insertion	2/5	ENST00000379044.5	NP_620689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARX	ENST00000379044.5	c.335_336insGGCGGC	p.Ala114_Ala115dup	inframe_insertion	2/5	1	NM_139058.3	ENSP00000368332	P1

Frequencies

GnomAD3 genomes AF: 0.000123 AC: 13 AN: 105434 Hom.: 0 Cov.: 22 AF XY: 0.0000970 AC XY: 3 AN XY: 30922

Gnomad AFR AF: 0.000202

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000309

Gnomad SAS AF: 0.000394

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000989

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000346 AC: 23 AN: 665304 Hom.: 0 Cov.: 31 AF XY: 0.0000346 AC XY: 7 AN XY: 202126

Gnomad4 AFR exome AF: 0.000155

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000448

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000776

Gnomad4 FIN exome AF: 0.000424

Gnomad4 NFE exome AF: 0.0000282

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.000123 AC: 13 AN: 105440 Hom.: 0 Cov.: 22 AF XY: 0.0000970 AC XY: 3 AN XY: 30934

Gnomad4 AFR AF: 0.000201

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000311

Gnomad4 SAS AF: 0.000396

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000989

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 15, 2019

The c.330_335dupGGCGGC variant (also known as p.A114_A115dup), located in coding exon 2 of the ARX gene, results from an in-frame duplication of GGCGGC at nucleotide positions 330 to 335. This results in the duplication of 2 extra residues (AA) between codons 114 and 115. This variant did not co-segregate with disease in one individual tested in our laboratory. These amino acid positions are not well conserved in available vertebrate species. This variant has been reported in individuals with neurodevelopmental disorders (Bienvenu T et al. Hum. Mol. Genet., 2002 Apr;11:981-91; Oegema R et al. Am. J. Med. Genet. A, 2012 Jun;158A:1472-6). In addition, this alteration is predicted to be neutral by in silico analysis (Choi Y et al., PLoS ONE 2012; 7(10):e46688). Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. -

ARX-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 19, 2023

The ARX c.330_335dup6 variant is predicted to result in an in-frame duplication (p.Ala114_Ala115dup). The predicted amino acid duplication (p.Ala114_Ala115dup) results in expansion of the ARX exon 2 polyalanine tract. This variant was described in a family with moderate X-linked disability (Family T80, reported as 304insGCGGCG, Bienvenu et al. 2002. PubMed ID: 11971879). In addition, this variant was reported in a male patient with seizures, cortical development abnormalities, infantile spasms, developmental delay, and hypotonia (referred to as 335ins6, Oegema et al. 2012. PubMed ID: 22585566). This variant has been observed in the hemizygous state in a general population database excluding individuals with severe pediatric disease (https://gnomad.broadinstitute.org/variant/X-25031776-T-TGCCGCC). However, population frequencies for variants within repetitive regions are not reliable due to technical limitations of next-generation sequencing, so it is unclear if this variant is present in unaffected males in the general population. Currently, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 21, 2022

This variant, c.330_335dup, results in the insertion of 2 amino acid(s) of the ARX protein (p.Ala114_Ala115dup), 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 been observed in individual(s) with infantile spasms, hemiplegia, and brain malformations (PMID: 11971879, 22585566). This variant is also known as 304ins(GCG)2 and c.335ins6. ClinVar contains an entry for this variant (Variation ID: 420027). 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. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 17, 2018

This variant is associated with the following publications: (PMID: 11971879, 22585566) -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs387906492; hg19: chrX-25031776;