rs1556046904

chrX-25004889-G-GGGGGCCATTGTGGAAAAGAGCCTGCAGGGAGAGCAAACAGCGCGGTCATGGCCTCGGGAGCTGTGCGCGGCGCCTCGGGCAGCGTCTCCCGCCGCTTGTCGCC

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_139058.3(ARX):c.1469_1470insGGCGACAAGCGGCGGGAGACGCTGCCCGAGGCGCCGCGCACAGCTCCCGAGGCCATGACCGCGCTGTTTGCTCTCCCTGCAGGCTCTTTTCCACAATGGCCCC(p.Leu491AlafsTer19) variant causes a stop gained, frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. P490P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 24)
• Consequence: ARX NM_139058.3 stop_gained, frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.99

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_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 14 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-25004889-G-GGGGGCCATTGTGGAAAAGAGCCTGCAGGGAGAGCAAACAGCGCGGTCATGGCCTCGGGAGCTGTGCGCGGCGCCTCGGGCAGCGTCTCCCGCCGCTTGTCGCC is Pathogenic according to our data. Variant chrX-25004889-G-GGGGGCCATTGTGGAAAAGAGCCTGCAGGGAGAGCAAACAGCGCGGTCATGGCCTCGGGAGCTGTGCGCGGCGCCTCGGGCAGCGTCTCCCGCCGCTTGTCGCC is described in ClinVar as [Pathogenic]. Clinvar id is 210320.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARX	NM_139058.3	c.1469_1470insGGCGACAAGCGGCGGGAGACGCTGCCCGAGGCGCCGCGCACAGCTCCCGAGGCCATGACCGCGCTGTTTGCTCTCCCTGCAGGCTCTTTTCCACAATGGCCCC	p.Leu491AlafsTer19	stop_gained, frameshift_variant	5/5	ENST00000379044.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARX	ENST00000379044.5	c.1469_1470insGGCGACAAGCGGCGGGAGACGCTGCCCGAGGCGCCGCGCACAGCTCCCGAGGCCATGACCGCGCTGTTTGCTCTCCCTGCAGGCTCTTTTCCACAATGGCCCC	p.Leu491AlafsTer19	stop_gained, frameshift_variant	5/5	1	NM_139058.3	P1
ARX	ENST00000636885.1	n.57_58insGGCGACAAGCGGCGGGAGACGCTGCCCGAGGCGCCGCGCACAGCTCCCGAGGCCATGACCGCGCTGTTTGCTCTCCCTGCAGGCTCTTTTCCACAATGGCCCC		non_coding_transcript_exon_variant	2/2	5

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked lissencephaly with abnormal genitalia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

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: rs1556046904; hg19: chrX-25023006;