rs748764628

chrX-25013437-C-AchrX-25013437-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_139058.3(ARX):c.558G>T(p.Pro186=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000346 in 933,518 control chromosomes in the GnomAD database, including 1 homozygotes. There are 96 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., 7 hem., cov: 22)
  • Exomes 𝑓: 0.00037 (1 hom. 89 hem.)
• Consequence: ARX NM_139058.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.917

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant X-25013437-C-A is Benign according to our data. Variant chrX-25013437-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 379128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-25013437-C-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.917 with no splicing effect.
• BS2: High Hemizygotes in GnomAd at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARX	NM_139058.3	c.558G>T	p.Pro186=	synonymous_variant	2/5	ENST00000379044.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARX	ENST00000379044.5	c.558G>T	p.Pro186=	synonymous_variant	2/5	1	NM_139058.3	P1

Frequencies

GnomAD3 genomes AF: 0.000195 AC: 21 AN: 107873 Hom.: 0 Cov.: 22 AF XY: 0.000221 AC XY: 7 AN XY: 31661

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000956

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000406

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000350

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000759 AC: 12 AN: 15800 Hom.: 0 AF XY: 0.000388 AC XY: 1 AN XY: 2580

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: 0.00174

Gnomad OTH exome AF: 0.00181

GnomAD4 exome AF: 0.000366 AC: 302 AN: 825645 Hom.: 1 Cov.: 31 AF XY: 0.000348 AC XY: 89 AN XY: 256087

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000366

Gnomad4 NFE exome AF: 0.000411

Gnomad4 OTH exome AF: 0.000217

GnomAD4 genome AF: 0.000195 AC: 21 AN: 107873 Hom.: 0 Cov.: 22 AF XY: 0.000221 AC XY: 7 AN XY: 31661

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000956

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000406

Gnomad4 NFE AF: 0.000350

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.000151

ClinVar

Significance: Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	ARX: BP4, BP7, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 09, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 30, 2016

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
Cadd	Benign	12
Dann	Benign	0.92

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: rs748764628; hg19: chrX-25031554;