rs587781234

Positions:

• chr15-25356842-AAAG-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PP4 PS4_Supporting PM6_Strong PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The p.Ser582del variant in UBE3A is absent from gnomAD (PM2_Supporting). The p.Ser582del variant in UBE3A has been reported in at least 2 de novo occurrences (biological parentage unconfirmed) in individuals with Angelman syndrome (PMID 25212744, internal database) (PM6_Strong). The p.Ser582del variant has been observed in at least 1 other individual with Angelman syndrome (PMID 25212744) (PS4_Supporting). The p.Ser582del variant in UBE3A has been reported in an individual with a clinical phenotype suggestive of Angelman syndrome (PMID 25212744) (PP4). In summary, the p.Ser582del variant in UBE3A is classified as likely pathogenic for Angelman syndrome based on the ACMG/AMP criteria (PM2_supporting, PM6_strong, PS4_supporting, PP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA333369/MONDO:0007113/016

• Frequency: Genomes: not found (cov: 32)
• Consequence: UBE3A NM_130839.5 disruptive_inframe_deletion
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 10.0

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 Likely_pathogenic. Variant got 7 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: 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.1805_1807delCTT	p.Ser602del	disruptive_inframe_deletion	8/13	ENST00000648336.2	NP_570854.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UBE3A	ENST00000648336.2	c.1805_1807delCTT	p.Ser602del	disruptive_inframe_deletion	8/13		NM_130839.5	ENSP00000497572.2

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: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

Angelman syndrome Pathogenic:4

Likely pathogenic, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Mar 26, 2021	The p.Ser582del variant in UBE3A is absent from gnomAD (PM2_Supporting). The p.Ser582del variant in UBE3A has been reported in at least 2 de novo occurrences (biological parentage unconfirmed) in individuals with Angelman syndrome (PMID 25212744, internal database) (PM6_Strong). The p.Ser582del variant has been observed in at least 1 other individual with Angelman syndrome (PMID 25212744) (PS4_Supporting). The p.Ser582del variant in UBE3A has been reported in an individual with a clinical phenotype suggestive of Angelman syndrome (PMID 25212744) (PP4). In summary, the p.Ser582del variant in UBE3A is classified as likely pathogenic for Angelman syndrome based on the ACMG/AMP criteria (PM2_supporting, PM6_strong, PS4_supporting, PP4). -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 27, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	Baylor Genetics	Feb 14, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 20, 2019	Experimental studies and prediction algorithms are not available or were not evaluated for this variant, and the functional significance of the affected amino acid(s) is currently unknown. This variant has been observed to be de novo in individuals with clinical features of Angelman syndrome (PMID: 25212744, 25693842). ClinVar contains an entry for this variant (Variation ID: 155987). This variant is not present in population databases (ExAC no frequency). This variant, c.1745_1747del, results in the deletion of 1 amino acid(s) of the UBE3A protein (p.Ser582del), but otherwise preserves the integrity of the reading frame. For these reasons, this variant has been classified as Pathogenic. -

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: rs587781234; hg19: chr15-25601989;