Variant X-25013659-TGCCGCCGCCGCCGCCGCCGCC-TGCCGCCGCCGCCGCCGCCGCCGCC details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP3BP6BS1BS2

The ENST00000379044.5(ARX):c.335_336insGGC(p.Ala114dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000506 in 770,684 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 82 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A112A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00052 ( 0 hom., 11 hem., cov: 22)

Exomes 𝑓: 0.00050 ( 0 hom. 71 hem. )

Consequence

ARX
ENST00000379044.5 inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:6

Conservation

PhyloP100: 1.33

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 -10 ACMG points.

BP3

Nonframeshift variant in repetitive region in ENST00000379044.5

BP6

Variant X-25013659-T-TGCC is Benign according to our data. Variant chrX-25013659-T-TGCC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 157755.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Likely_benign=3, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000522 (55/105439) while in subpopulation SAS AF= 0.000792 (2/2524). AF 95% confidence interval is 0.000444. There are 0 homozygotes in gnomad4. There are 11 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 11 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARX	NM_139058.3 linkuse as main transcript	c.335_336insGGC	p.Ala114dup	inframe_insertion	2/5	ENST00000379044.5	NP_620689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARX	ENST00000379044.5 linkuse as main transcript	c.335_336insGGC	p.Ala114dup	inframe_insertion	2/5	1	NM_139058.3	ENSP00000368332	P1

Frequencies

GnomAD3 genomes

AF:

0.000522

AC:

AN:

105433

Hom.:

Cov.:

AF XY:

0.000356

AC XY:

AN XY:

30921

show subpopulations

Gnomad AFR

AF:

0.000672

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000970

Gnomad ASJ

AF:

0.000784

Gnomad EAS

AF:

0.000618

Gnomad SAS

AF:

0.000788

Gnomad FIN

AF:

0.000237

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000514

Gnomad OTH

AF:

0.000692

GnomAD4 exome

AF:

0.000504

AC:

335

AN:

665245

Hom.:

Cov.:

AF XY:

0.000351

AC XY:

AN XY:

202077

show subpopulations

Gnomad4 AFR exome

AF:

0.000387

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000235

Gnomad4 SAS exome

AF:

0.000388

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000517

Gnomad4 OTH exome

AF:

0.000400

GnomAD4 genome

AF:

0.000522

AC:

AN:

105439

Hom.:

Cov.:

AF XY:

0.000356

AC XY:

AN XY:

30933

show subpopulations

Gnomad4 AFR

AF:

0.000671

Gnomad4 AMR

AF:

0.0000969

Gnomad4 ASJ

AF:

0.000784

Gnomad4 EAS

AF:

0.000621

Gnomad4 SAS

AF:

0.000792

Gnomad4 FIN

AF:

0.000237

Gnomad4 NFE

AF:

0.000514

Gnomad4 OTH

AF:

0.000683

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	ARX: BP3 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 06, 2023	See Variant Classification Assertion Criteria. -
Uncertain significance, no assertion criteria provided	clinical testing	Eurofins Ntd Llc (ga)	Mar 18, 2014	- -

ARX-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 12, 2023

The ARX c.333_335dupGGC variant is predicted to result in an in-frame duplication (p.Ala115dup). This variant was reported as a maternally-inherited variant in two unrelated male individuals with intellectual disability/developmental delay (reported as c.333_334ins(GCG) in patients #39589 and #41263, Gronskov et al. 2004. PubMed ID: 15199382). However, this variant was not found in a similarly affected family member of the patient #39589 but was identified in an unaffected male control in the same study, suggested by the author that this variant is a rare polymorphism. This variant is reported in 0.078% of alleles in individuals of African descent in gnomAD and has been documented in a hemizygous individual (http://gnomad.broadinstitute.org/variant/X-25031776-T-TGCC). In ClinVar, this variant has conflicting interpretations ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/157755/). This variant falls within a low complexity region, therefore the allele frequency data should be interpreted with caution. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 11, 2014

- -

Developmental and epileptic encephalopathy, 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 17, 2023

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. -

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 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