rs1556056154
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM4PP5_Moderate
The NM_139058.3(ARX):c.458_459insAGGGGCCGCCGCGGCAGCCGCGGCCGCGGCCGC(p.Gly143_Ala153dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 706,679 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 22)
Exomes 𝑓: 0.0000014 ( 0 hom. 0 hem. )
Consequence
ARX
NM_139058.3 inframe_insertion
NM_139058.3 inframe_insertion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.53
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 6 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PM4
?
Nonframeshift variant in NON repetitive region in NM_139058.3.
PP5
?
Variant X-25013536-G-GGCGGCCGCGGCCGCGGCTGCCGCGGCGGCCCCT is Pathogenic according to our data. Variant chrX-25013536-G-GGCGGCCGCGGCCGCGGCTGCCGCGGCGGCCCCT is described in ClinVar as [Pathogenic]. Clinvar id is 473011.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.458_459insAGGGGCCGCCGCGGCAGCCGCGGCCGCGGCCGC | p.Gly143_Ala153dup | inframe_insertion | 2/5 | ENST00000379044.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ARX | ENST00000379044.5 | c.458_459insAGGGGCCGCCGCGGCAGCCGCGGCCGCGGCCGC | p.Gly143_Ala153dup | inframe_insertion | 2/5 | 1 | NM_139058.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 22
GnomAD3 genomes
?
Cov.:
22
GnomAD4 exome AF: 0.00000142 AC: 1AN: 706679Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 214469
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706679
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31
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GnomAD4 genome ? Cov.: 22
GnomAD4 genome
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Cov.:
22
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Intellectual disability, X-linked, with or without seizures, arx-related;C3463992:Developmental and epileptic encephalopathy, 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 13, 2022 | ClinVar contains an entry for this variant (Variation ID: 473011). This variant results in expansion of a poly-alanine tract in ARX. Expansions of the alanine tracts in ARX have been observed in individuals with ARX-related conditions (PMID: 11889467, 17664401, 23246292). For these reasons, this variant has been classified as Pathogenic. This variant is also known as c.423_455dup33, c.424_453dup, and dup33. This variant, c.426_458dup, results in the insertion of 11 amino acid(s) of the ARX protein (p.Gly143_Ala153dup), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. This variant has been observed in individual(s) with X-linked intellectual disability and neurological disorders (PMID: 19507262). It has also been observed to segregate with disease in related individuals. - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at