Variant X-25013543-GCGGCCGCGGCTGCCGCGGCGGCCC-GCGGCCGCGGCTGCCGCGGCGGCCCCGGCCGCGGCTGCCGCGGCGGCCC details in Genebe, Genetics Data Aggregator

Variant summary

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

The ENST00000379044.5(ARX):c.451_452insGGGCCGCCGCGGCAGCCGCGGCCG(p.Gly143_Ala150dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000189 in 794,926 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A151A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000077 ( 0 hom., 0 hem., cov: 21)

Exomes 𝑓: 0.000010 ( 0 hom. 2 hem. )

Consequence

ARX
ENST00000379044.5 inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:1

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 Likely_benign. Variant got -1 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in ENST00000379044.5.

PP5

Variant X-25013543-G-GCGGCCGCGGCTGCCGCGGCGGCCC is Pathogenic according to our data. Variant chrX-25013543-G-GCGGCCGCGGCTGCCGCGGCGGCCC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 11187.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.

BS2

High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARX	NM_139058.3 linkuse as main transcript	c.451_452insGGGCCGCCGCGGCAGCCGCGGCCG	p.Gly143_Ala150dup	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.451_452insGGGCCGCCGCGGCAGCCGCGGCCG	p.Gly143_Ala150dup	inframe_insertion	2/5	1	NM_139058.3	ENSP00000368332	P1

Frequencies

GnomAD3 genomes

AF:

0.0000767

AC:

AN:

104289

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

29767

show subpopulations

Gnomad AFR

AF:

0.000237

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:

0.0000200

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000101

AC:

AN:

690637

Hom.:

Cov.:

AF XY:

0.00000954

AC XY:

AN XY:

209747

show subpopulations

Gnomad4 AFR exome

AF:

0.000226

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000664

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000484

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000767

AC:

AN:

104289

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

29767

show subpopulations

Gnomad4 AFR

AF:

0.000237

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:

0.0000200

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 1

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 04, 2007

- -

Intellectual disability, X-linked, with or without seizures, arx-related

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 04, 2007

- -

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 18, 2024

This variant, c.428_451dup, results in the insertion of 8 amino acid(s) of the ARX protein (p.Gly143_Ala150dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs387906493, gnomAD 0.02%). This variant has been observed in individual(s) with ARX-related conditions (PMID: 16235064, 20506206, 21204215, 26029707). It has also been observed to segregate with disease in related individuals. This variant is also known as c.441_464 and dup24. ClinVar contains an entry for this variant (Variation ID: 11187). Studies have shown that this variant alters ARX gene expression (PMID: 17331656). For these reasons, this variant has been classified as Pathogenic. -

Partington syndrome

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 04, 2007

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 14, 2024

In-frame duplication of one Glycine and 7 Alanine residues in the second polyalanine tract of the ARX protein; Has not been previously published as pathogenic or benign to our knowledge; Observed in hemizygous state in two patients referred for epilepsy genetic testing at GeneDx and not observed in hemizygous state in controls; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20300201) -

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