rs587783207

Positions:

• chrX-25015650-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_139058.3(ARX):​c.88G>T​(p.Asp30Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D30E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 24)
• Consequence: ARX NM_139058.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.94

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.904

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARX	NM_139058.3	c.88G>T	p.Asp30Tyr	missense_variant	1/5	ENST00000379044.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARX	ENST00000379044.5	c.88G>T	p.Asp30Tyr	missense_variant	1/5	1	NM_139058.3	P1
ARX	ENST00000636609.1	n.36-5G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		5
ARX	ENST00000637394.1	n.68-5G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

epileptic encephalopathy, early infanitle, 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.53	D
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Uncertain	2.0	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.74
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.83
MutPred		0.39		Gain of MoRF binding (P = 0.0432);
MVP		0.98
MPC		1.4
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.94
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs587783207; hg19: chrX-25033767; COSMIC: COSV66874794;