X-25007238-A-AGGCGGC

Position:

• chrX-25007238-A-AGGCGGC

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP3 BP6 BS2

The NM_139058.3(ARX):​c.1320_1321insGCCGCC​(p.Ala439_Ala440dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000754 in 1,126,822 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 24 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000082 (0 hom. 24 hem.)
• Consequence: ARX NM_139058.3 inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 2.21

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 Likely_benign. Variant got -6 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_139058.3
• BP6: Variant X-25007238-A-AGGCGGC is Benign according to our data. Variant chrX-25007238-A-AGGCGGC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 516395.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=2}.
• BS2: High Hemizygotes in GnomAdExome4 at 24 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARX	NM_139058.3	c.1320_1321insGCCGCC	p.Ala439_Ala440dup	inframe_insertion	4/5	ENST00000379044.5	NP_620689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARX	ENST00000379044.5	c.1320_1321insGCCGCC	p.Ala439_Ala440dup	inframe_insertion	4/5	1	NM_139058.3	ENSP00000368332	P1

Frequencies

GnomAD3 genomes AF: 0.0000180 AC: 2 AN: 111037 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33353

Gnomad AFR AF: 0.0000328

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000168

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000817 AC: 83 AN: 1015785 Hom.: 0 Cov.: 32 AF XY: 0.0000740 AC XY: 24 AN XY: 324265

Gnomad4 AFR exome AF: 0.0000907

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000222

Gnomad4 FIN exome AF: 0.000132

Gnomad4 NFE exome AF: 0.0000904

Gnomad4 OTH exome AF: 0.0000702

GnomAD4 genome AF: 0.0000180 AC: 2 AN: 111037 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33353

Gnomad4 AFR AF: 0.0000328

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000168

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 10, 2020	This variant is associated with the following publications: (PMID: 30496128) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2020	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 10, 2022

The c.1315_1320dupGCCGCC (p.A439_A440dup) alteration is located in exon 4 (coding exon 4) of the ARX gene. The alteration consists of an in-frame duplication of 6 nucleotides from position 1315 to 1320, resulting in the duplication of <NA> residues. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 21, 2022

This variant, c.1315_1320dup, results in the insertion of 2 amino acid(s) of the ARX protein (p.Ala439_Ala440dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (no rsID available, gnomAD 0.01%), including at least one homozygous and/or hemizygous individual. This variant has been observed in individuals with clinical features of epileptic encephalopathy (Invitae). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

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: rs398124508; hg19: chrX-25025355;