Genetic Variant ARX:p.Gly143_Ala150dup (chrX-25013543-G-GCGGCCGCGGCTGCCGCGGCGGCCC) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

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

The NM_139058.3(ARX):c.428_451dupGGGCCGCCGCGGCAGCCGCGGCCG(p.Gly143_Ala150dup) variant causes a conservative 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).

Frequency

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

Exomes 𝑓: 0.000010 ( 0 hom. 2 hem. )

Consequence

ARX
NM_139058.3 conservative_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 NM_139058.3.

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: {Uncertain_significance=1, Pathogenic=1}.

BS2

High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARX	NM_139058.3 link	c.428_451dupGGGCCGCCGCGGCAGCCGCGGCCG	p.Gly143_Ala150dup	conservative_inframe_insertion	Exon 2 of 5	ENST00000379044.5	NP_620689.1	Q96QS3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARX	ENST00000379044.5 link	c.428_451dupGGGCCGCCGCGGCAGCCGCGGCCG	p.Gly143_Ala150dup	conservative_inframe_insertion	Exon 2 of 5	1	NM_139058.3	ENSP00000368332.4		Q96QS3

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

May 04, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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

Pathogenic:1

May 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

May 04, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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

Pathogenic:1

May 04, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided

Uncertain:1

Feb 14, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

X-25013543-GCGGCCGCGGCTGCCGCGGCGGCCC-GCGGCCGCGGCTGCCGCGGCGGCCCCGGCCGCGGCTGCCGCGGCGGCCC

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