X-25013659-TGCCGCCGCCGCCGCCGCCGCC-TGCCGCCGCCGCC

Position:

• chrX-25013659-TGCCGCCGCCGCCGCCGCCGCC-TGCCGCCGCCGCC

Variant summary

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

The NM_139058.3(ARX):​c.327_335delGGCGGCGGC​(p.Ala110_Ala112del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000477 in 770,724 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 118 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., 7 hem., cov: 22)
  • Exomes 𝑓: 0.00052 (0 hom. 111 hem.)
• Consequence: ARX NM_139058.3 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 3.39

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-TGCCGCCGCC-T is Benign according to our data. Variant chrX-25013659-TGCCGCCGCC-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 473009.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000516 (343/665285) while in subpopulation NFE AF= 0.000552 (333/603244). AF 95% confidence interval is 0.000502. There are 0 homozygotes in gnomad4_exome. There are 111 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARX	NM_139058.3	c.327_335delGGCGGCGGC	p.Ala110_Ala112del	disruptive_inframe_deletion	2/5	ENST00000379044.5	NP_620689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARX	ENST00000379044.5	c.327_335delGGCGGCGGC	p.Ala110_Ala112del	disruptive_inframe_deletion	2/5	1	NM_139058.3	ENSP00000368332.4

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 25 AN: 105433 Hom.: 0 Cov.: 22 AF XY: 0.000226 AC XY: 7 AN XY: 30921

Gnomad AFR AF: 0.000235

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000970

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000309

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000297

Gnomad OTH AF: 0.000692

GnomAD4 exome AF: 0.000516 AC: 343 AN: 665285 Hom.: 0 AF XY: 0.000549 AC XY: 111 AN XY: 202107

Gnomad4 AFR exome AF: 0.000232

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000235

Gnomad4 SAS exome AF: 0.0000776

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000552

Gnomad4 OTH exome AF: 0.000222

GnomAD4 genome AF: 0.000237 AC: 25 AN: 105439 Hom.: 0 Cov.: 22 AF XY: 0.000226 AC XY: 7 AN XY: 30933

Gnomad4 AFR AF: 0.000235

Gnomad4 AMR AF: 0.0000969

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000311

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000297

Gnomad4 OTH AF: 0.000683

Bravo AF: 0.000223

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 10, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	ARX: BP3 -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 24, 2020	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 17, 2021

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

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;