rs587784527

Positions:

• chr15-25339185-CTCTT-C
• chr15-25339185-CTCTT-CTCTTTCTT

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM6 PVS1 PS4 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The p.Lys836Argfs variant in UBE3A is predicted to cause a premature stop codon that leads to a truncated 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). This variant has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with Angelman syndrome (PMID 9887341) (PM6). This variant has been observed in at least 4 other individuals with Angelman syndrome (PMID 9887341, 25212744, ClinVar) (PS4). The p.Lys836Argfs variant in UBE3A is absent from gnomAD (PM2_supporting). In summary, the p.Lys836Argfs variant in UBE3A is classified as Pathogenic for Angelman syndrome based on the ACMG/AMP criteria (PVS1, PS4, PM6, PM2_supporting). LINK:https://erepo.genome.network/evrepo/ui/classification/CA333552/MONDO:0007113/016

• Frequency: Genomes: not found (cov: 32)
• Consequence: UBE3A NM_130839.5 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:17 U:1
• Conservation: PhyloP100: 8.02

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:):

ACMG classification

Verdict is Pathogenic. Variant got 15 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.
• PM6: 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.2567_2570delAAGA	p.Lys856fs	frameshift_variant	13/13	ENST00000648336.2	NP_570854.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UBE3A	ENST00000648336.2	c.2567_2570delAAGA	p.Lys856fs	frameshift_variant	13/13		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: Pathogenic

Submissions summary: Pathogenic:17 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Angelman syndrome Pathogenic:11 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Génétique des Maladies du Développement, Hospices Civils de Lyon	Apr 27, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 08, 2024	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function on the maternal allele is a known mechanism of disease in this gene and is associated with Angelman syndrome (MIM#105830). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0113 - This gene is known to be imprinted, which results in the silencing of the paternal allele (PMID: 20301323). (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0600 - Variant is located in the annotated HECT ubiquitin-transferase domain (DECIPHER). (I) 0702 - Other truncating variants comparable to the one identified in this case have strong previous evidence for pathogenicity. There are multiple downstream truncating variants reported as pathogenic (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic in ClinVar by the ClinGen variant curation expert panel for Rett and Angelman-like disorders. (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 01, 2017	This variant has been previously reported as disease-causing and was found once in our laboratory de novo in a 2-year-old male with global delays, absent speech, hypertonia, strabismus. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Apr 23, 2007	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 30, 2004	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Mar 26, 2021	The p.Lys836Argfs variant in UBE3A is predicted to cause a premature stop codon that leads to a truncated 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). This variant has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with Angelman syndrome (PMID 9887341) (PM6). This variant has been observed in at least 4 other individuals with Angelman syndrome (PMID 9887341, 25212744, ClinVar) (PS4). The p.Lys836Argfs variant in UBE3A is absent from gnomAD (PM2_supporting). In summary, the p.Lys836Argfs variant in UBE3A is classified as Pathogenic for Angelman syndrome based on the ACMG/AMP criteria (PVS1, PS4, PM6, PM2_supporting). -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Nov 29, 2021	PVS1, PS2, PS4, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 14, 2022	ClinVar contains an entry for this variant (Variation ID: 160220). For these reasons, this variant has been classified as Pathogenic. This variant is also known as c.3093del4. This premature translational stop signal has been observed in individual(s) with Angelman syndrome (PMID: 9887341, 19213023). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys836Argfs*4) in the UBE3A gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 17 amino acid(s) of the UBE3A protein. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Apr 04, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine	Feb 18, 2021	- -
Pathogenic, criteria provided, single submitter	research	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Oct 04, 2024	PVS1,PS4,PM2 -

not provided Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 22, 2022	Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 17 amino acids are lost and replaced with 3 incorrect amino acids (HGMD); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9887341, 25212744, 19213023, 31031587, 27535533) -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2017	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 18, 2022

The c.2507_2510delAAGA (p.K836Rfs*4) alteration, located in exon 10 (coding exon 10) of the UBE3A gene, consists of a deletion of 4 nucleotides from position 2507 to 2510, causing a translational frameshift with a predicted alternate stop codon after 4 amino acids. This alteration occurs at the 3' terminus of the UBE3A gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 26 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration (also designated as 3093del4 and 3093delAAGA) has been reported as a de novo mutation in multiple patients meeting clinical criteria for Angelman syndrome (Fang, 1999; Rapakko, 2004; Hitchins, 2004; Camprubí, 2009; Tzagkaraki, 2013; Sadikovic, 2014; Xiong, 2019). Based on the available evidence, this alteration is classified as pathogenic. -

Intellectual disability Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Diagnostic Laboratory, Strasbourg University Hospital

Sep 10, 2020

- -

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: rs587784527; hg19: chr15-25584332;