rs190910161

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_ModerateBP6BP7BS1BS2

The NM_139058.3(ARX):c.1671G>A(p.Thr557=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00406 in 1,164,057 control chromosomes in the GnomAD database, including 7 homozygotes. There are 1,540 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0033 ( 1 hom., 126 hem., cov: 25)

Exomes 𝑓: 0.0041 ( 6 hom. 1414 hem. )

Consequence

ARX
NM_139058.3 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:10

Conservation

PhyloP100: 0.0630

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.44).

BP6

Variant X-25004688-C-T is Benign according to our data. Variant chrX-25004688-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 96453.We mark this variant Likely_benign, oryginal submissions are: {Benign=6, Uncertain_significance=1}. Variant chrX-25004688-C-T is described in Lovd as [Likely_benign]. Variant chrX-25004688-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.063 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00332 (376/113309) while in subpopulation NFE AF= 0.00525 (280/53294). AF 95% confidence interval is 0.00475. There are 1 homozygotes in gnomad4. There are 126 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd at 126 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARX	NM_139058.3 linkuse as main transcript	c.1671G>A	p.Thr557=	synonymous_variant	5/5	ENST00000379044.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARX	ENST00000379044.5 linkuse as main transcript	c.1671G>A	p.Thr557=	synonymous_variant	5/5	1	NM_139058.3	P1

Frequencies

GnomAD3 genomes

AF:

0.00332

AC:

376

AN:

113263

Hom.:

Cov.:

AF XY:

0.00356

AC XY:

126

AN XY:

35419

show subpopulations

Gnomad AFR

AF:

0.000672

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000734

Gnomad ASJ

AF:

0.000376

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00980

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00525

Gnomad OTH

AF:

0.00261

GnomAD3 exomes

AF:

0.00299

AC:

314

AN:

105177

Hom.:

AF XY:

0.00280

AC XY:

103

AN XY:

36819

show subpopulations

Gnomad AFR exome

AF:

0.000346

Gnomad AMR exome

AF:

0.000571

Gnomad ASJ exome

AF:

0.000497

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000716

Gnomad FIN exome

AF:

0.00691

Gnomad NFE exome

AF:

0.00560

Gnomad OTH exome

AF:

0.00293

GnomAD4 exome

AF:

0.00414

AC:

4345

AN:

1050748

Hom.:

Cov.:

AF XY:

0.00412

AC XY:

1414

AN XY:

343046

show subpopulations

Gnomad4 AFR exome

AF:

0.000725

Gnomad4 AMR exome

AF:

0.000610

Gnomad4 ASJ exome

AF:

0.000323

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000201

Gnomad4 FIN exome

AF:

0.00819

Gnomad4 NFE exome

AF:

0.00472

Gnomad4 OTH exome

AF:

0.00325

GnomAD4 genome

AF:

0.00332

AC:

376

AN:

113309

Hom.:

Cov.:

AF XY:

0.00355

AC XY:

126

AN XY:

35475

show subpopulations

Gnomad4 AFR

AF:

0.000671

Gnomad4 AMR

AF:

0.000733

Gnomad4 ASJ

AF:

0.000376

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00980

Gnomad4 NFE

AF:

0.00525

Gnomad4 OTH

AF:

0.00258

Alfa

AF:

0.00429

Hom.:

Bravo

AF:

0.00245

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2016	- -

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 07, 2012	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 07, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

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

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 25, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 22, 2017

This alteration is classified as 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.44

Cadd

Benign

Dann

Benign

0.82

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over