Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PP5_Moderate
The NM_130839.5(UBE3A):c.2535_2551delACTTCCGGAATACTCAA(p.Leu846GlnfsTer5) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★).
UBE3A (HGNC:12496): (ubiquitin protein ligase E3A) This gene encodes an E3 ubiquitin-protein ligase, part of the ubiquitin protein degradation system. This imprinted gene is maternally expressed in brain and biallelically expressed in other tissues. Maternally inherited deletion of this gene causes Angelman Syndrome, characterized by severe motor and intellectual retardation, ataxia, hypotonia, epilepsy, absence of speech, and characteristic facies. The protein also interacts with the E6 protein of human papillomavirus types 16 and 18, resulting in ubiquitination and proteolysis of tumor protein p53. Alternative splicing of this gene results in three transcript variants encoding three isoforms with different N-termini. Additional transcript variants have been described, but their full length nature has not been determined. [provided by RefSeq, Jul 2008]
SNHG14 (HGNC:37462): (small nucleolar RNA host gene 14) This gene is located within the Prader-Willi critical region and produces a long, spliced paternally-imprinted RNA that initiates within a common upstream promoter region shared by the SNRPN (small nuclear ribonucleoprotein polypeptide N) and SNURF genes. This transcript serves as a host RNA for the small nucleolar RNA, C/D box 115 and 116 clusters. This RNA extends in antisense into the region of the ubiquitin protein ligase E3A gene (UBE3A), and is thought to regulate imprinted expression of UBE3A in the brain. This transcript undergoes extensive alternative splicing, and may initiate and terminate at multiple locations within this genomic region. The full-length structure of all splice forms is not determined. [provided by RefSeq, Mar 2017]
Our verdict: Pathogenic. The variant received 10 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 40 pathogenic variants in the truncated region.
PP5
Variant 15-25339204-CTTGAGTATTCCGGAAGT-C is Pathogenic according to our data. Variant chr15-25339204-CTTGAGTATTCCGGAAGT-C is described in ClinVar as Pathogenic. ClinVar VariationId is 408432.Status of the report is criteria_provided_single_submitter, 1 stars.
This sequence change deletes 17 nucleotides in exon 10 of the UBE3A mRNA (c.2475_2491delACTTCCGGAATACTCAA), causing a frameshift at codon 826. This creates a premature translational stop signal in the last exon of the UBE3A mRNA (p.Leu826Glnfs*5). While this is not anticipated to result in nonsense mediated decay, it is expected to result in a truncated UBE3A protein. While this particular variant has not been reported in the literature, maternally-inherited truncating variants in UBE3A are known to be pathogenic (PMID: 25212744). In addition, several frameshift variants that occur downstream of this variant have been reported in affected individuals (PMID: 25212744). For these reasons, this variant has been classified as Pathogenic. -