X-25013659-TGCCGCCGCCGCCGCCGCCGCC-TGCCGCC

Variant names:

• chrX-25013659-TGCCGCCGCCGCCGCC-T
• rs387906492
• NM_139058.3:c.321_335delGGCGGCGGCGGCGGC

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP3 BP6 BS2

The NM_139058.3(ARX):​c.321_335delGGCGGCGGCGGCGGC​(p.Ala108_Ala112del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 665,300 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.000018 (0 hom. 4 hem.)
  • Failed GnomAD Quality Control
• Consequence: ARX NM_139058.3 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 3.39
• 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: 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: Likely_benign. The variant received -6 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_139058.3
• BP6: Variant X-25013659-TGCCGCCGCCGCCGCC-T is Benign according to our data. Variant chrX-25013659-TGCCGCCGCCGCCGCC-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 591328.
• BS2: High AC in GnomAdExome4 at 12 XL,AD 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.321_335delGGCGGCGGCGGCGGC	p.Ala108_Ala112del	disruptive_inframe_deletion	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.321_335delGGCGGCGGCGGCGGC	p.Ala108_Ala112del	disruptive_inframe_deletion	Exon 2 of 5	ENSP00000368332.4	Q96QS3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 105433 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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000180 AC: 12 AN: 665300 Hom.: 0 AF XY: 0.0000198 AC XY: 4 AN XY: 202122

African (AFR) AF: 0.00 AC: 0 AN: 12912

American (AMR) AF: 0.00 AC: 0 AN: 1456

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4467

East Asian (EAS) AF: 0.00 AC: 0 AN: 4251

South Asian (SAS) AF: 0.00 AC: 0 AN: 12884

European-Finnish (FIN) AF: 0.000424 AC: 1 AN: 2358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1204

European-Non Finnish (NFE) AF: 0.0000182 AC: 11 AN: 603255

Other (OTH) AF: 0.00 AC: 0 AN: 22513

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 105433 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 30921

African (AFR) AF: 0.00 AC: 0 AN: 29751

American (AMR) AF: 0.00 AC: 0 AN: 10307

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2550

East Asian (EAS) AF: 0.00 AC: 0 AN: 3236

South Asian (SAS) AF: 0.00 AC: 0 AN: 2537

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4216

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 208

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 50542

Other (OTH) AF: 0.00 AC: 0 AN: 1446

Alfa AF: 0.00 Hom.: 2

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	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		3.4

Splicing

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

Other links and lift over

dbSNP: rs387906492; hg19: chrX-25031776;