X-25013529-AGGCCGCGGC-AGGCCGCGGCGGCCGCGGC

Variant names:

• chrX-25013529-A-AGGCCGCGGC
• rs797045302
• NM_139058.3:c.457_465dupGCCGCGGCC

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM4 BS2

The NM_139058.3(ARX):​c.457_465dupGCCGCGGCC​(p.Ala153_Ala155dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000998 in 701,721 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000097 (0 hom., 1 hem., cov: 22)
  • Exomes 𝑓: 0.000010 (0 hom. 3 hem.)
  • Failed GnomAD Quality Control
• Consequence: ARX NM_139058.3 conservative_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.708
• Publications: 0 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: 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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_139058.3.
• BS2: High AC in GnomAdExome4 at 7 AD,XL gene.

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.457_465dupGCCGCGGCC	p.Ala153_Ala155dup	conservative_inframe_insertion	Exon 2 of 5	NP_620689.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARX	ENST00000379044.5	TSL:1 MANE Select	c.457_465dupGCCGCGGCC	p.Ala153_Ala155dup	conservative_inframe_insertion	Exon 2 of 5	ENSP00000368332.4

Frequencies

GnomAD3 genomes AF: 0.00000973 AC: 1 AN: 102826 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000450

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000998 AC: 7 AN: 701721 Hom.: 0 Cov.: 31 AF XY: 0.0000143 AC XY: 3 AN XY: 210279

African (AFR) AF: 0.00 AC: 0 AN: 13441

American (AMR) AF: 0.00 AC: 0 AN: 2354

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5901

East Asian (EAS) AF: 0.00 AC: 0 AN: 6339

South Asian (SAS) AF: 0.000429 AC: 7 AN: 16307

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4723

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1371

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 626881

Other (OTH) AF: 0.00 AC: 0 AN: 24404

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000973 AC: 1 AN: 102826 Hom.: 0 Cov.: 22 AF XY: 0.0000344 AC XY: 1 AN XY: 29088

African (AFR) AF: 0.00 AC: 0 AN: 29120

American (AMR) AF: 0.00 AC: 0 AN: 10058

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2551

East Asian (EAS) AF: 0.00 AC: 0 AN: 3013

South Asian (SAS) AF: 0.000450 AC: 1 AN: 2222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3765

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 49863

Other (OTH) AF: 0.00 AC: 0 AN: 1400

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

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		0.71

Splicing

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

Other links and lift over

dbSNP: rs797045302; hg19: chrX-25031646;