rs398122854

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5

The NM_139058.3(ARX):​c.81C>G​(p.Tyr27Ter) variant causes a stop gained 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 Likely pathogenic (no stars).

Frequency

Genomes: not found (cov: 24)

Consequence

ARX
NM_139058.3 stop_gained

Scores

2
2
1

Clinical Significance

Pathogenic/Likely pathogenic no assertion criteria provided P:2

Conservation

PhyloP100: 5.79
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.952 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant X-25015657-G-C is Pathogenic according to our data. Variant chrX-25015657-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 29964.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ARXNM_139058.3 linkuse as main transcriptc.81C>G p.Tyr27Ter stop_gained 1/5 ENST00000379044.5 NP_620689.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ARXENST00000379044.5 linkuse as main transcriptc.81C>G p.Tyr27Ter stop_gained 1/51 NM_139058.3 ENSP00000368332 P1
ARXENST00000636609.1 linkuse as main transcriptn.36-12C>G splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant 5
ARXENST00000637394.1 linkuse as main transcriptn.68-12C>G 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: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 1 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMFeb 01, 2010- -
Intellectual disability, X-linked, with or without seizures, arx-related Pathogenic:1
Likely pathogenic, no assertion criteria providedclinical testingGenomics England Pilot Project, Genomics England-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.74
D
BayesDel_noAF
Pathogenic
0.63
CADD
Pathogenic
37
DANN
Uncertain
1.0
FATHMM_MKL
Uncertain
0.93
D
MutationTaster
Benign
1.0
A
Vest4
0.85
GERP RS
5.2

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.16
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs398122854; hg19: chrX-25033774; API