X-25013659-TGCCGCCGCCGCCGCCGCCGCC-TGCCGCCGCCGCCGCCGCCGCCGCC

Variant names:

• chrX-25013659-T-TGCC
• rs387906492
• NM_139058.3:c.333_335dupGGC

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP3 BP6 BS1 BS2

The NM_139058.3(ARX):​c.333_335dupGGC​(p.Ala112dup) variant causes a disruptive 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).

• Frequency:
  • Genomes: 𝑓 0.00052 (0 hom., 11 hem., cov: 22)
  • Exomes 𝑓: 0.00050 (0 hom. 71 hem.)
• Consequence: ARX NM_139058.3 disruptive_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: 1.33

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 -10 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_139058.3
• 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: {Likely_benign=3, 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 rank	MANE	Protein	UniProt
ARX	NM_139058.3	c.333_335dupGGC	p.Ala112dup	disruptive_inframe_insertion	Exon 2 of 5	ENST00000379044.5	NP_620689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARX	ENST00000379044.5	c.333_335dupGGC	p.Ala112dup	disruptive_inframe_insertion	Exon 2 of 5	1	NM_139058.3	ENSP00000368332.4

Frequencies

GnomAD3 genomes AF: 0.000522 AC: 55 AN: 105433 Hom.: 0 Cov.: 22 AF XY: 0.000356 AC XY: 11 AN XY: 30921

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.: 0 Cov.: 31 AF XY: 0.000351 AC XY: 71 AN XY: 202077

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: 55 AN: 105439 Hom.: 0 Cov.: 22 AF XY: 0.000356 AC XY: 11 AN XY: 30933

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:2 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ARX: BP3 -

Mar 18, 2014

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 06, 2023

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

ARX-related disorder Uncertain:1

Oct 12, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 11, 2014

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Developmental and epileptic encephalopathy, 1 Benign:1

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Sep 27, 2024

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 24, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs387906492; hg19: chrX-25031776;