rs1556056125

chrX-25013533-C-CGCGGCGGCCGCGGCCGCGGCTGCCGCG

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM4 PP5

The NM_139058.3(ARX):c.461_462insCGCGGCAGCCGCGGCCGCGGCCGCCGC(p.Ala147_Ala155dup) variant causes a 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 Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. A154A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 21)
• Consequence: ARX NM_139058.3 inframe_insertion
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.30

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_139058.3.
• PP5: Variant X-25013533-C-CGCGGCGGCCGCGGCCGCGGCTGCCGCG is Pathogenic according to our data. Variant chrX-25013533-C-CGCGGCGGCCGCGGCCGCGGCTGCCGCG is described in ClinVar as [Pathogenic]. Clinvar id is 29963.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARX	NM_139058.3	c.461_462insCGCGGCAGCCGCGGCCGCGGCCGCCGC	p.Ala147_Ala155dup	inframe_insertion	2/5	ENST00000379044.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARX	ENST00000379044.5	c.461_462insCGCGGCAGCCGCGGCCGCGGCCGCCGC	p.Ala147_Ala155dup	inframe_insertion	2/5	1	NM_139058.3	P1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 21

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Developmental and epileptic encephalopathy, 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 2009

- -

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: rs1556056125; hg19: chrX-25031650;