Variant X-25007238-AGGCGGCGGC-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP3BP6BS2

The NM_139058.3(ARX):c.1312_1320del(p.Ala438_Ala440del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000115 in 1,126,823 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000012 ( 0 hom. 5 hem. )

Consequence

ARX
NM_139058.3 inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 2.72

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 Likely_benign. Variant got -6 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_139058.3

BP6

Variant X-25007238-AGGCGGCGGC-A is Benign according to our data. Variant chrX-25007238-AGGCGGCGGC-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1014281.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS2

High Hemizygotes in GnomAdExome4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARX	NM_139058.3 linkuse as main transcript	c.1312_1320del	p.Ala438_Ala440del	inframe_deletion	4/5	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.1312_1320del	p.Ala438_Ala440del	inframe_deletion	4/5	1	NM_139058.3	ENSP00000368332	P1

Frequencies

GnomAD3 genomes

AF:

0.00000901

AC:

AN:

111037

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33353

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:

0.0000190

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000315

AC:

AN:

63404

Hom.:

AF XY:

0.0000613

AC XY:

AN XY:

16306

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000762

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000118

AC:

AN:

1015786

Hom.:

AF XY:

0.0000154

AC XY:

AN XY:

324268

show subpopulations

Gnomad4 AFR exome

AF:

0.0000453

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:

0.0000136

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000901

AC:

AN:

111037

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33353

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:

0.0000190

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

ARX-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 25, 2024

The ARX c.1312_1320del9 variant is predicted to result in an in-frame deletion (p.Ala438_Ala440del). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0082% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, 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

Aug 28, 2021

This variant, c.1312_1320del, results in the deletion of 3 amino acid(s) of the ARX protein (p.Ala438_Ala440del), 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 ExAC database. This variant has not been reported in the literature in individuals affected with ARX-related conditions. 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

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2023

ARX: BP3 -

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