rs398124512

chrX-25013536-GGCGGCC-GchrX-25013536-GGCGGCC-GGCGGCCGCGGCC

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2 PM4 BP6_Moderate

The NM_139058.3(ARX):c.453_458del(p.Ala154_Ala155del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000283 in 706,674 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. A151A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.0000028 (0 hom. 0 hem.)
• Consequence: ARX NM_139058.3 inframe_deletion
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.95

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_139058.3.
• BP6: Variant X-25013536-GGCGGCC-G is Benign according to our data. Variant chrX-25013536-GGCGGCC-G is described in ClinVar as [Likely_benign]. Clinvar id is 1996210.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARX	NM_139058.3	c.453_458del	p.Ala154_Ala155del	inframe_deletion	2/5	ENST00000379044.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARX	ENST00000379044.5	c.453_458del	p.Ala154_Ala155del	inframe_deletion	2/5	1	NM_139058.3	P1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome AF: 0.00000283 AC: 2 AN: 706674 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 214464

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000636

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000159

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 21

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Invitae

May 19, 2022

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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: rs398124512; hg19: chrX-25031653;