Variant X-25013536-GGCGGCC-GGCGGCCGCGGCC details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM4PP5BS2

The NM_139058.3(ARX):c.458_459insGGCCGC(p.Ala154_Ala155dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000259 in 811,267 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 0.000048 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000023 ( 0 hom. 5 hem. )

Consequence

ARX
NM_139058.3 inframe_insertion

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 1.53

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 -1 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_139058.3.

PP5

Variant X-25013536-G-GGCGGCC is Pathogenic according to our data. Variant chrX-25013536-G-GGCGGCC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 96456.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

BS2

High Hemizygotes in GnomAdExome4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARX	NM_139058.3 linkuse as main transcript	c.458_459insGGCCGC	p.Ala154_Ala155dup	inframe_insertion	2/5	ENST00000379044.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARX	ENST00000379044.5 linkuse as main transcript	c.458_459insGGCCGC	p.Ala154_Ala155dup	inframe_insertion	2/5	1	NM_139058.3	P1

Frequencies

GnomAD3 genomes

AF:

0.0000478

AC:

AN:

104588

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

29912

show subpopulations

Gnomad AFR

AF:

0.000169

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000226

AC:

AN:

706679

Hom.:

Cov.:

AF XY:

0.0000233

AC XY:

AN XY:

214469

show subpopulations

Gnomad4 AFR exome

AF:

0.000733

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:

0.00000952

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000478

AC:

AN:

104588

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

29912

show subpopulations

Gnomad4 AFR

AF:

0.000169

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:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2020	Alanine repeat expansion in the second polyalanine tract of the ARX protein, extending the allele to 14 repeats; Polyalanine repeat expansions of 12 or fewer repeats have been observed in unaffected adult males undergoing testing at GeneDx; Polyalanine repeat expansions of 13-19 repeats have not been previously reported in the literature, to our knowledge (Stenson et al., 2014) -
Uncertain significance, no assertion criteria provided	clinical testing	Eurofins Ntd Llc (ga)	Sep 26, 2013	- -

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

Invitae

Oct 25, 2022

This variant, c.453_458dup, results in the insertion of 2 amino acid(s) of the ARX protein (p.Ala154_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 not been reported in the literature in individuals affected with ARX-related conditions. ClinVar contains an entry for this variant (Variation ID: 96456). 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. -

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