Variant X-25013530-GGCCGCGGCGGCCGCGGCCGCGGCT-GGCCGCGGCGGCCGCGGCCGCGGCTGCCGCGGCGGCCGCGGCCGCGGCT details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PM4PP5_Very_Strong

The NM_139058.3(ARX):c.464_465insAGCCGCGGCCGCGGCCGCCGCGGC(p.Ala148_Ala155dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000246 in 813,857 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000096 ( 0 hom., 0 hem., cov: 21)

Exomes 𝑓: 0.0000014 ( 0 hom. 0 hem. )

Consequence

ARX
NM_139058.3 inframe_insertion

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 0.378

Variant links:

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]

ARX links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 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-25013530-G-GGCCGCGGCGGCCGCGGCCGCGGCT is Pathogenic according to our data. Variant chrX-25013530-G-GGCCGCGGCGGCCGCGGCCGCGGCT is described in ClinVar as [Pathogenic]. Clinvar id is 96455.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARX	NM_139058.3 linkuse as main transcript	c.464_465insAGCCGCGGCCGCGGCCGCCGCGGC	p.Ala148_Ala155dup	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 linkuse as main transcript	c.464_465insAGCCGCGGCCGCGGCCGCCGCGGC	p.Ala148_Ala155dup	inframe_insertion	2/5	1	NM_139058.3	ENSP00000368332	P1

Frequencies

GnomAD3 genomes

AF:

0.00000955

AC:

AN:

104668

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

29916

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000199

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000141

AC:

AN:

709189

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

214631

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000158

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000955

AC:

AN:

104668

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

29916

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000199

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Jun 17, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 08, 2016	This variant is the most common pathogenic repeat allele of the second poly-alanine tract (called PA2) within exon 2 of the ARX gene. This repeat allele has been reported with various nomenclatures in multiple individuals with ARX-related diseases including intellectual disability and X-linked infantile spasm syndrome among others.1-4 References: Kato et al. Am J Hum Genet. 2007 Aug;81(2):361-6. Stromme et al. Nat Genet. 2002 Apr;30(4):441-5 Gronskov et al. Eur J Hum Genet. 2004 Sep;12(9):701-5 Marques et al. Mol Genet Genomic Med. 2015 May;3(3):203-14 -
Pathogenic, no assertion criteria provided	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jan 30, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 29, 2022	Alanine repeat expansion in the second polyalanine tract of the ARX protein, extending the allele to 20 repeats; Published functional studies demonstrate a damaging effect as expansions in the second polyalanine repeat track are suggested to interfere with ARX-related regulation of KDM5C resulting in the misregulation of numerous downstream processes (Poeta et al., 2013); Not observed in unaffected adult males referred for testing at GeneDx; This variant is associated with the following publications: (PMID: 22922607, 11889467, 24528893, 26029707, 24781210, 23246292, 12874418) -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 02, 2024

This variant, c.441_464dup, results in the insertion of 8 amino acid(s) of the ARX protein (p.Ala148_Ala155dup), 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 insufficient coverage at this position in the gnomAD database. This variant has been observed in individual(s) with Partington-like syndrome, West syndrome, and/or infantile spasms (PMID: 12874418, 22922607, 24781210, 26029707). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 96455). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on ARX function (PMID: 23246292). This variant results in expansion of a poly-alanine tract in ARX. Expansions of the alanine tracts in ARX have been observed in individuals with ARX-related conditions (PMID: 11889467, 17664401, 23246292). For these reasons, this variant has been classified as Pathogenic. -

X-linked lissencephaly with abnormal genitalia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 02, 2014

- -

Corpus callosum agenesis-abnormal genitalia syndrome;C0796244:Intellectual disability, X-linked, with or without seizures, arx-related;C0796250:Partington syndrome;C1846171:X-linked lissencephaly with abnormal genitalia;C3463992:Developmental and epileptic encephalopathy, 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Genetics Lab, CHRU Brest

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over