NM_139058.3:c.333_335delGGC

Variant names:

• chrX-25013659-TGCC-T
• rs387906492
• NM_139058.3:c.333_335delGGC

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BS1 BS2

The NM_139058.3(ARX):​c.333_335delGGC​(p.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 0.000915 in 760,402 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 62 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A111A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., 6 hem., cov: 22)
  • Exomes 𝑓: 0.0010 (0 hom. 56 hem.)
• Consequence: ARX NM_139058.3 disruptive_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.33
• 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: Benign. The variant received -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_139058.3
• BP6: Variant X-25013659-TGCC-T is Benign according to our data. Variant chrX-25013659-TGCC-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 416368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000247 (26/105432) while in subpopulation EAS AF = 0.00124 (4/3218). AF 95% confidence interval is 0.000424. There are 0 homozygotes in GnomAd4. There are 6 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High AC in GnomAd4 at 26 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.333_335delGGC	p.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.333_335delGGC	p.Ala112del	disruptive_inframe_deletion	Exon 2 of 5	ENSP00000368332.4	Q96QS3

Frequencies

GnomAD3 genomes AF: 0.000247 AC: 26 AN: 105426 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.000471

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000970

Gnomad ASJ AF: 0.000392

Gnomad EAS AF: 0.00124

Gnomad SAS AF: 0.000394

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000989

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 6

Gnomad NFE exome AF: 0.00

GnomAD4 exome AF: 0.00102 AC: 670 AN: 654970 Hom.: 0 AF XY: 0.000285 AC XY: 56 AN XY: 196330

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00142 AC: 18 AN: 12714

American (AMR) AF: 0.00800 AC: 11 AN: 1375

Ashkenazi Jewish (ASJ) AF: 0.00252 AC: 11 AN: 4368

East Asian (EAS) AF: 0.00419 AC: 17 AN: 4053

South Asian (SAS) AF: 0.000633 AC: 8 AN: 12636

European-Finnish (FIN) AF: 0.0105 AC: 23 AN: 2194

Middle Eastern (MID) AF: 0.00341 AC: 4 AN: 1172

European-Non Finnish (NFE) AF: 0.000909 AC: 540 AN: 594345

Other (OTH) AF: 0.00172 AC: 38 AN: 22113

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000247 AC: 26 AN: 105432 Hom.: 0 Cov.: 22 AF XY: 0.000194 AC XY: 6 AN XY: 30934

African (AFR) AF: 0.000470 AC: 14 AN: 29785

American (AMR) AF: 0.0000969 AC: 1 AN: 10315

Ashkenazi Jewish (ASJ) AF: 0.000392 AC: 1 AN: 2550

East Asian (EAS) AF: 0.00124 AC: 4 AN: 3218

South Asian (SAS) AF: 0.000396 AC: 1 AN: 2524

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4214

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 187

European-Non Finnish (NFE) AF: 0.0000989 AC: 5 AN: 50535

Other (OTH) AF: 0.00 AC: 0 AN: 1464

Alfa AF: 0.000266 Hom.: 2

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs387906492; hg19: chrX-25031776; COSMIC: COSV109439288; COSMIC: COSV109439288;