X-25013659-TGCCGCCGCCGCCGCCGCCGCC-TGCCGCCGCCGCCGCCGCC

Position:

• chrX-25013659-TGCCGCCGCCGCCGCCGCCGCC-TGCCGCCGCCGCCGCCGCC

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BS1 BS2

The NM_139058.3(ARX):​c.333_335del​(p.Ala115del) variant causes a 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 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.33

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARX	NM_139058.3	c.333_335del	p.Ala115del	inframe_deletion	2/5	ENST00000379044.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARX	ENST00000379044.5	c.333_335del	p.Ala115del	inframe_deletion	2/5	1	NM_139058.3	P1

Frequencies

GnomAD3 genomes AF: 0.000247 AC: 26 AN: 105426 Hom.: 0 Cov.: 22 AF XY: 0.000194 AC XY: 6 AN XY: 30922

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

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

Gnomad4 AFR exome AF: 0.00142

Gnomad4 AMR exome AF: 0.00800

Gnomad4 ASJ exome AF: 0.00252

Gnomad4 EAS exome AF: 0.00419

Gnomad4 SAS exome AF: 0.000633

Gnomad4 FIN exome AF: 0.0105

Gnomad4 NFE exome AF: 0.000909

Gnomad4 OTH exome AF: 0.00172

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

Gnomad4 AFR AF: 0.000470

Gnomad4 AMR AF: 0.0000969

Gnomad4 ASJ AF: 0.000392

Gnomad4 EAS AF: 0.00124

Gnomad4 SAS AF: 0.000396

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000989

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 13, 2021

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 17, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

ARX-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 10, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 21, 2020

This variant is associated with the following publications: (PMID: 32613771) -

Intellectual disability, X-linked, with or without seizures, arx-related;C3463992:Developmental and epileptic encephalopathy, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs387906492; hg19: chrX-25031776;