NM_139058.3:c.1315_1320delGCCGCC

Variant names:

• chrX-25007238-AGGCGGC-A
• rs398124508
• NM_139058.3:c.1315_1320delGCCGCC

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.1315_1320delGCCGCC​(p.Ala439_Ala440del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000158 in 1,015,758 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.000016 (0 hom. 4 hem.)
• Consequence: ARX NM_139058.3 conservative_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.72
• 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: Likely_benign. The variant received -6 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_139058.3
• BP6: Variant X-25007238-AGGCGGC-A is Benign according to our data. Variant chrX-25007238-AGGCGGC-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1210879.
• BS2: High AC in GnomAdExome4 at 16 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.1315_1320delGCCGCC	p.Ala439_Ala440del	conservative_inframe_deletion	Exon 4 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.1315_1320delGCCGCC	p.Ala439_Ala440del	conservative_inframe_deletion	Exon 4 of 5	ENSP00000368332.4	Q96QS3
	ARX	ENST00000637993.1	TSL:5	c.-75_-70delGCCGCC		upstream_gene	N/A	ENSP00000490122.1	A0A1B0GUI3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.0000158 AC: 16 AN: 1015758 Hom.: 0 AF XY: 0.0000123 AC XY: 4 AN XY: 324248

African (AFR) AF: 0.00 AC: 0 AN: 22057

American (AMR) AF: 0.00 AC: 0 AN: 22182

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16879

East Asian (EAS) AF: 0.00 AC: 0 AN: 25477

South Asian (SAS) AF: 0.00 AC: 0 AN: 44942

European-Finnish (FIN) AF: 0.0000331 AC: 1 AN: 30245

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3716

European-Non Finnish (NFE) AF: 0.0000186 AC: 15 AN: 807500

Other (OTH) AF: 0.00 AC: 0 AN: 42760

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 1

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Intellectual disability, X-linked, with or without seizures, ARX-related;C3463992:Developmental and epileptic encephalopathy, 1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.7

Splicing

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

Other links and lift over

dbSNP: rs398124508; hg19: chrX-25025355;