chrX-25013543-G-GCGGCCGCGGCTGCCGCGGCGGCCC
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM4PP5BS2
The NM_139058.3(ARX):c.451_452insGGGCCGCCGCGGCAGCCGCGGCCG(p.Gly143_Ala150dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000189 in 794,926 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A151A) has been classified as Likely benign.
Frequency
Consequence
NM_139058.3 inframe_insertion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ARX | NM_139058.3 | c.451_452insGGGCCGCCGCGGCAGCCGCGGCCG | p.Gly143_Ala150dup | inframe_insertion | 2/5 | ENST00000379044.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ARX | ENST00000379044.5 | c.451_452insGGGCCGCCGCGGCAGCCGCGGCCG | p.Gly143_Ala150dup | inframe_insertion | 2/5 | 1 | NM_139058.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000767 AC: 8AN: 104289Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0AN XY: 29767
GnomAD4 exome AF: 0.0000101 AC: 7AN: 690637Hom.: 0 Cov.: 30 AF XY: 0.00000954 AC XY: 2AN XY: 209747
GnomAD4 genome AF: 0.0000767 AC: 8AN: 104289Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0AN XY: 29767
ClinVar
Submissions by phenotype
Developmental and epileptic encephalopathy, 1 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 04, 2007 | - - |
Intellectual disability, X-linked, with or without seizures, arx-related Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 04, 2007 | - - |
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 | Jan 18, 2024 | This variant, c.428_451dup, results in the insertion of 8 amino acid(s) of the ARX protein (p.Gly143_Ala150dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs387906493, gnomAD 0.02%). This variant has been observed in individual(s) with ARX-related conditions (PMID: 16235064, 20506206, 21204215, 26029707). It has also been observed to segregate with disease in related individuals. This variant is also known as c.441_464 and dup24. ClinVar contains an entry for this variant (Variation ID: 11187). Studies have shown that this variant alters ARX gene expression (PMID: 17331656). For these reasons, this variant has been classified as Pathogenic. - |
Partington syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 04, 2007 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 28, 2018 | The c.428_451dup24 variant in the ARX gene has been reported multiple times previously in association with ARX-related disorders (Strømme et al., 2002; Stepp et al., 2005; Laperuta et al., 2007). The c.428_451dup24 variant results in an in-frame addition of 8 Alanine residues in the second polyalanine tract of ARX, leading to a protein with 20 Alanine repeats instead of the normal 12 repeats. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. We consider it to be a variant of uncertain significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at