rs1556056125

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM4PP5

The NM_139058.3(ARX):​c.435_461dupCGCGGCAGCCGCGGCCGCGGCCGCCGC​(p.Ala146_Ala154dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. A154A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 21)

Consequence

ARX
NM_139058.3 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 3.30

Publications

1 publications found
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 Gene-Disease associations (from GenCC):
  • genetic developmental and epileptic encephalopathy
    Inheritance: XL, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
  • intellectual disability, X-linked, with or without seizures, ARX-related
    Inheritance: XL Classification: DEFINITIVE, MODERATE Submitted by: Ambry Genetics, G2P
  • Partington syndrome
    Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
  • X-linked complex neurodevelopmental disorder
    Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
  • X-linked lissencephaly with abnormal genitalia
    Inheritance: XL Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
  • infantile spasms
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • corpus callosum agenesis-abnormal genitalia syndrome
    Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
  • infantile epileptic-dyskinetic encephalopathy
    Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
  • non-syndromic X-linked intellectual disability
    Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
  • X-linked spasticity-intellectual disability-epilepsy syndrome
    Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM4
Nonframeshift variant in NON repetitive region in NM_139058.3.
PP5
Variant X-25013533-C-CGCGGCGGCCGCGGCCGCGGCTGCCGCG is Pathogenic according to our data. Variant chrX-25013533-C-CGCGGCGGCCGCGGCCGCGGCTGCCGCG is described in ClinVar as Pathogenic. ClinVar VariationId is 29963.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ARXNM_139058.3 linkc.435_461dupCGCGGCAGCCGCGGCCGCGGCCGCCGC p.Ala146_Ala154dup disruptive_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
ARXENST00000379044.5 linkc.435_461dupCGCGGCAGCCGCGGCCGCGGCCGCCGC p.Ala146_Ala154dup disruptive_inframe_insertion Exon 2 of 5 1 NM_139058.3 ENSP00000368332.4 Q96QS3

Frequencies

GnomAD3 genomes
Cov.:
21
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
21

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 1 Pathogenic:1
Aug 01, 2009
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

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Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
3.3
Mutation Taster
=68/32
disease causing (ClinVar)

Splicing

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

Publications

Other links and lift over

dbSNP: rs1556056125; hg19: chrX-25031650; API