rs111033595

Positions:

• chr15-25340219-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2_Supporting PS4_Supporting PVS1 PP1 PP4

This summary comes from the ClinGen Evidence Repository: The p.Trp768Ter variant in UBE3A is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). The p.Trp768Ter variant in the UBE3A gene is absent from gnomAD (PM2_supporting). The p.Trp768Ter variant in UBE3A has been reported in an individual with a clinical phenotype suggestive of Angelman syndrome (PMID 9792887) (PP1). This variant has been observed in at least 1 other individuals with Angelman syndrome (PMID 29915382) (PS4_supporting). The variant has been reported to segregate in two informative meioses (PMID 9792887) (PP1). In summary, the p.Trp768Ter variant in UBE3A is classified as Pathogenic for Angelman syndrome based on the ACMG/AMP criteria (PVS1, PS4_supporting, PM2_supporting, PP1, PP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA325622/MONDO:0007113/016

• Frequency: Genomes: not found (cov: 32)
• Consequence: UBE3A NM_130839.5 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 7.91

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 12 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UBE3A	NM_130839.5	c.2364G>A	p.Trp788Ter	stop_gained	12/13	ENST00000648336.2	NP_570854.1
SNHG14	NR_146177.1	n.18393-51377C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UBE3A	ENST00000648336.2	c.2364G>A	p.Trp788Ter	stop_gained	12/13		NM_130839.5	ENSP00000497572	P1
SNHG14	ENST00000656420.1	n.5456+61335C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Angelman syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 05, 2015	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Mar 01, 2021	The p.Trp768Ter variant in UBE3A is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). The p.Trp768Ter variant in the UBE3A gene is absent from gnomAD (PM2_supporting). The p.Trp768Ter variant in UBE3A has been reported in an individual with a clinical phenotype suggestive of Angelman syndrome (PMID 9792887) (PP1). This variant has been observed in at least 1 other individuals with Angelman syndrome (PMID 29915382) (PS4_supporting). The variant has been reported to segregate in two informative meioses (PMID 9792887) (PP1). In summary, the p.Trp768Ter variant in UBE3A is classified as Pathogenic for Angelman syndrome based on the ACMG/AMP criteria (PVS1, PS4_supporting, PM2_supporting, PP1, PP4). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 1998	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	53
DANN	Uncertain	1.0
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	A;A;A;A;A
Vest4		0.97, 0.96, 0.97
GERP RS		5.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.72		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.72		Position offset: -23

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs111033595; hg19: chr15-25585366;