3-132665825-G-A
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong
The NM_024818.6(UBA5):c.164G>A(p.Arg55His) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,461,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R55C) has been classified as Uncertain significance.
Frequency
Consequence
NM_024818.6 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
UBA5 | NM_024818.6 | c.164G>A | p.Arg55His | missense_variant, splice_region_variant | 2/12 | ENST00000356232.10 | |
NPHP3-ACAD11 | NR_037804.1 | n.3995+16089C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
UBA5 | ENST00000356232.10 | c.164G>A | p.Arg55His | missense_variant, splice_region_variant | 2/12 | 1 | NM_024818.6 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000548 AC: 8AN: 1461038Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 726818
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 04, 2022 | Published functional studies demonstrate reduced UBA5 activity (Muona et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27545674, 29286531) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 21, 2021 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects UBA5 function (PMID: 27545674). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). ClinVar contains an entry for this variant (Variation ID: 265746). This missense change has been observed in individual(s) with early infantile epileptic encephalopathy (PMID: 27545674, 29286531). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs774318611, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 55 of the UBA5 protein (p.Arg55His). - |
Developmental and epileptic encephalopathy, 44 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 10, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at