rs398124510

Positions:

• chrX-25013530-GGCCGCGGCGGCCGCGGCCGCGGCT-G
• chrX-25013530-GGCCGCGGCGGCCGCGGCCGCGGCT-GGCCGCGGCGGCCGCGGCCGCGGCTGCCGCGGCGGCCGCGGCCGCGGCT

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM4 BP6_Very_Strong BS1 BS2

The NM_139058.3(ARX):​c.441_464del​(p.Ala148_Ala155del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000533 in 813,782 control chromosomes in the GnomAD database, including 2 homozygotes. There are 124 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00071 (0 hom., 25 hem., cov: 21)
  • Exomes 𝑓: 0.00051 (2 hom. 99 hem.)
• Consequence: ARX NM_139058.3 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:7
• Conservation: PhyloP100: 3.30

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 -14 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_139058.3.
• BP6: Variant X-25013530-GGCCGCGGCGGCCGCGGCCGCGGCT-G is Benign according to our data. Variant chrX-25013530-GGCCGCGGCGGCCGCGGCCGCGGCT-G is described in ClinVar as [Likely_benign]. Clinvar id is 96454.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-25013530-GGCCGCGGCGGCCGCGGCCGCGGCT-G is described in Lovd as [Pathogenic].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000707 (74/104652) while in subpopulation AMR AF= 0.000879 (9/10236). AF 95% confidence interval is 0.000613. There are 0 homozygotes in gnomad4. There are 25 alleles in male gnomad4 subpopulation. Median coverage is 21. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 25 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARX	NM_139058.3	c.441_464del	p.Ala148_Ala155del	inframe_deletion	2/5	ENST00000379044.5	NP_620689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARX	ENST00000379044.5	c.441_464del	p.Ala148_Ala155del	inframe_deletion	2/5	1	NM_139058.3	ENSP00000368332	P1

Frequencies

GnomAD3 genomes AF: 0.000707 AC: 74 AN: 104666 Hom.: 0 Cov.: 21 AF XY: 0.000836 AC XY: 25 AN XY: 29914

Gnomad AFR AF: 0.000877

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000880

Gnomad ASJ AF: 0.000391

Gnomad EAS AF: 0.000612

Gnomad SAS AF: 0.000402

Gnomad FIN AF: 0.000253

Gnomad MID AF: 0.00457

Gnomad NFE AF: 0.000597

Gnomad OTH AF: 0.00211

GnomAD3 exomes AF: 0.000393 AC: 1 AN: 2544 Hom.: 0 AF XY: 0.00314 AC XY: 1 AN XY: 318

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000801

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000508 AC: 360 AN: 709130 Hom.: 2 AF XY: 0.000461 AC XY: 99 AN XY: 214590

Gnomad4 AFR exome AF: 0.00153

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000342

Gnomad4 EAS exome AF: 0.000611

Gnomad4 SAS exome AF: 0.00101

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000473

Gnomad4 OTH exome AF: 0.000683

GnomAD4 genome AF: 0.000707 AC: 74 AN: 104652 Hom.: 0 Cov.: 21 AF XY: 0.000836 AC XY: 25 AN XY: 29920

Gnomad4 AFR AF: 0.000876

Gnomad4 AMR AF: 0.000879

Gnomad4 ASJ AF: 0.000391

Gnomad4 EAS AF: 0.000615

Gnomad4 SAS AF: 0.000405

Gnomad4 FIN AF: 0.000253

Gnomad4 NFE AF: 0.000597

Gnomad4 OTH AF: 0.00209

Alfa AF: 0.00114 Hom.: 4

Bravo AF: 0.000824

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 04, 2013	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	ARX: BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Intellectual disability, X-linked, with or without seizures, arx-related Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Jan 01, 2011

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 02, 2019

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. -

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs398124510; hg19: chrX-25031647;