rs587780570

chr15-25371798-TTAAG-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_130839.5(UBE3A):c.372_375del(p.Tyr124Ter) variant causes a frameshift change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: UBE3A NM_130839.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 9.32

Genes affected

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 15-25371798-TTAAG-T is Pathogenic according to our data. Variant chr15-25371798-TTAAG-T is described in ClinVar as [Pathogenic]. Clinvar id is 136192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-25371798-TTAAG-T is described in Lovd as [Pathogenic]. Variant chr15-25371798-TTAAG-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UBE3A	NM_130839.5	c.372_375del	p.Tyr124Ter	frameshift_variant	6/13	ENST00000648336.2
SNHG14	NR_146177.1	n.18393-19792_18393-19789del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UBE3A	ENST00000648336.2	c.372_375del	p.Tyr124Ter	frameshift_variant	6/13		NM_130839.5	P1
SNHG14	ENST00000656420.1	n.5457-46984_5457-46981del		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Angelman syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Pathogenic, no assertion criteria provided	clinical testing	Baylor Genetics	Feb 14, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neurogenetics Laboratory - MEYER, AOU Meyer	Nov 16, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 30, 2020	For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with clinical features of UBE3A-related conditions (PMID: 25212744). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Tyr104*) in the UBE3A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in UBE3A are known to be pathogenic (PMID: 25212744). -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 20, 2023	Reported in a cohort of individuals with suspected Angelman syndrome, however clinical information was not provided (Sadikovic et al., 2014); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28569743, 25212744) -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

Other links and lift over

dbSNP: rs587780570; hg19: chr15-25616945;