chrX-25013530-GGCCGCGGCGGCCGCGGCCGCGGCT-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PM4BP6_Very_StrongBS1BS2

The NM_139058.3(ARX):c.441_464delAGCCGCGGCCGCGGCCGCCGCGGC(p.Ala148_Ala155del) variant causes a disruptive 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. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. 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 disruptive_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 was made for transcript

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 21. This position passed quality control check.

BS2

High AC in GnomAd4 at 74 XLR,XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARX	NM_139058.3 link	c.441_464delAGCCGCGGCCGCGGCCGCCGCGGC	p.Ala148_Ala155del	disruptive_inframe_deletion	Exon 2 of 5	ENST00000379044.5	NP_620689.1	Q96QS3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARX	ENST00000379044.5 link	c.441_464delAGCCGCGGCCGCGGCCGCCGCGGC	p.Ala148_Ala155del	disruptive_inframe_deletion	Exon 2 of 5	1	NM_139058.3	ENSP00000368332.4		Q96QS3

Frequencies

GnomAD3 genomes

AF:

0.000707

AC:

AN:

104666

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.000393

AC:

AN:

2544

AF XY:

0.00314

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 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

African (AFR)

AF:

0.00153

AC:

AN:

13697

American (AMR)

AF:

0.00

AC:

AN:

2561

Ashkenazi Jewish (ASJ)

AF:

0.000342

AC:

AN:

5850

East Asian (EAS)

AF:

0.000611

AC:

AN:

6549

South Asian (SAS)

AF:

0.00101

AC:

AN:

15769

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6202

Middle Eastern (MID)

AF:

0.000724

AC:

AN:

1381

European-Non Finnish (NFE)

AF:

0.000473

AC:

299

AN:

632232

Other (OTH)

AF:

0.000683

AC:

AN:

24889

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.533

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000707

AC:

AN:

104652

Hom.:

Cov.:

AF XY:

0.000836

AC XY:

AN XY:

29920

show subpopulations

African (AFR)

AF:

0.000876

AC:

AN:

29667

American (AMR)

AF:

0.000879

AC:

AN:

10236

Ashkenazi Jewish (ASJ)

AF:

0.000391

AC:

AN:

2560

East Asian (EAS)

AF:

0.000615

AC:

AN:

3253

South Asian (SAS)

AF:

0.000405

AC:

AN:

2470

European-Finnish (FIN)

AF:

0.000253

AC:

AN:

3946

Middle Eastern (MID)

AF:

0.00510

AC:

AN:

196

European-Non Finnish (NFE)

AF:

0.000597

AC:

AN:

50258

Other (OTH)

AF:

0.00209

AC:

AN:

1433

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 04, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ARX: BS2 -

Intellectual disability, X-linked, with or without seizures, ARX-related

Uncertain:1

Jan 01, 2011

OMIM

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Inborn genetic diseases

Benign:1

Mar 02, 2019

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.3

Mutation Taster

=191/9

polymorphism

(source)

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 for variant X:25013530 GGCCGCGGCGGCCGCGGCCGCGGCT>G . It may be empty.

chrX-25013530-GGCCGCGGCGGCCGCGGCCGCGGCT-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over