X-25013659-TGCCGCCGCCGCCGCCGCCGCC-TGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCC

Position:

• chrX-25013659-TGCCGCCGCCGCCGCCGCCGCC-TGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCC

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP3

The NM_139058.3(ARX):​c.321_335dupGGCGGCGGCGGCGGC​(p.Ala108_Ala112dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: ARX NM_139058.3 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U: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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP3: Nonframeshift variant in repetitive region in NM_139058.3

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARX	NM_139058.3	c.321_335dupGGCGGCGGCGGCGGC	p.Ala108_Ala112dup	disruptive_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.321_335dupGGCGGCGGCGGCGGC	p.Ala108_Ala112dup	disruptive_inframe_insertion	2/5	1	NM_139058.3	ENSP00000368332.4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 03, 2018

Alanine repeat expansion in the first polyalanine tract of the ARX protein, extending the allele to 21 repeats; Polyalanine repeat expansions of 18 or fewer repeats have been observed in unaffected adult males in population databases and undergoing testing at GeneDx (Lek et al., 2015); Polyalanine repeat expansions of 21-22 repeats have not been previously reported in the literature to our knowledge (Stenson et al., 2014); Not observed in large population cohorts (Lek et al., 2016) -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-25031776;