rs398124510

Positions:

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM4BP6_Very_StrongBS1BS2

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 (★★). Synonymous variant affecting the same amino acid position (i.e. A147A) has been classified 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

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:7

Conservation

PhyloP100: 3.30

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:

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ACMG classification

Classification made for transcript

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	UniProt
ARX	NM_139058.3 linkuse as main transcript	c.441_464del	p.Ala148_Ala155del	inframe_deletion	2/5	ENST00000379044.5

Ensembl

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

Frequencies

GnomAD3 genomes

AF:

0.000707

AC:

AN:

104666

Hom.:

Cov.:

AF XY:

0.000836

AC XY:

AN XY:

29914

show subpopulations

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:

AN:

2544

Hom.:

AF XY:

0.00314

AC XY:

AN XY:

318

show subpopulations

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.:

AF XY:

0.000461

AC XY:

AN XY:

214590

show subpopulations

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:

AN:

104652

Hom.:

Cov.:

AF XY:

0.000836

AC XY:

AN XY:

29920

show subpopulations

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.:

Bravo

AF:

0.000824

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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