NM_139058.3:c.426_458dupAGGGGCCGCCGCGGCAGCCGCGGCCGCGGCCGC

Variant names:

• chrX-25013536-G-GGCGGCCGCGGCCGCGGCTGCCGCGGCGGCCCCT
• rs1556056154
• NM_139058.3:c.426_458dupAGGGGCCGCCGCGGCAGCCGCGGCCGCGGCCGC

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM4 PP5_Moderate

The NM_139058.3(ARX):​c.426_458dupAGGGGCCGCCGCGGCAGCCGCGGCCGCGGCCGC​(p.Ala153_Ala154insGlyAlaAlaAlaAlaAlaAlaAlaAlaAlaAla) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 706,679 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 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 (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000014 (0 hom. 0 hem.)
• Consequence: ARX NM_139058.3 disruptive_inframe_insertion
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.53
• Publications: 1 publications found

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: AD, XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• 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: Orphanet, G2P
• 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: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_139058.3.
• PP5: Variant X-25013536-G-GGCGGCCGCGGCCGCGGCTGCCGCGGCGGCCCCT is Pathogenic according to our data. Variant chrX-25013536-G-GGCGGCCGCGGCCGCGGCTGCCGCGGCGGCCCCT is described in ClinVar as Pathogenic. ClinVar VariationId is 473011.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_139058.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARX	NM_139058.3	MANE Select	c.426_458dupAGGGGCCGCCGCGGCAGCCGCGGCCGCGGCCGC	p.Ala153_Ala154insGlyAlaAlaAlaAlaAlaAlaAlaAlaAlaAla	disruptive_inframe_insertion	Exon 2 of 5	NP_620689.1	Q96QS3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARX	ENST00000379044.5	TSL:1 MANE Select	c.426_458dupAGGGGCCGCCGCGGCAGCCGCGGCCGCGGCCGC	p.Ala153_Ala154insGlyAlaAlaAlaAlaAlaAlaAlaAlaAlaAla	disruptive_inframe_insertion	Exon 2 of 5	ENSP00000368332.4	Q96QS3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000142 AC: 1 AN: 706679 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 214469

African (AFR) AF: 0.00 AC: 0 AN: 13636

American (AMR) AF: 0.00 AC: 0 AN: 2499

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5778

East Asian (EAS) AF: 0.00 AC: 0 AN: 6383

South Asian (SAS) AF: 0.00 AC: 0 AN: 15719

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6042

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1372

European-Non Finnish (NFE) AF: 0.00000159 AC: 1 AN: 630488

Other (OTH) AF: 0.00 AC: 0 AN: 24762

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Intellectual disability, X-linked, with or without seizures, ARX-related;C3463992:Developmental and epileptic encephalopathy, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.5
Mutation Taster		=66/34	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1556056154; hg19: chrX-25031653;