rs587784527

Variant names:

• chr15-25339185-CTCTT-C
• rs587784527
• NM_130839.5:c.2567_2570delAAGA

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

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

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: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 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 rank	MANE	Protein	UniProt
UBE3A	NM_130839.5	c.2567_2570delAAGA	p.Lys856ArgfsTer4	frameshift_variant	Exon 13 of 13	ENST00000648336.2	NP_570854.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UBE3A	ENST00000648336.2	c.2567_2570delAAGA	p.Lys856ArgfsTer4	frameshift_variant	Exon 13 of 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

Oct 04, 2024

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PVS1,PS4,PM2 -

Apr 27, 2017

Génétique des Maladies du Développement, Hospices Civils de Lyon

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2017

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 30, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nov 29, 2021

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PS2, PS4, PM2 -

Mar 26, 2021

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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). -

Oct 08, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Apr 23, 2007

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 18, 2021

Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This variant is not present in population databases (gnomAD no frequency). 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 also known as c.3093del4. ClinVar contains an entry for this variant (Variation ID: 160220). For these reasons, this variant has been classified as Pathogenic. -

Apr 04, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:4

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 22, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Feb 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Jul 18, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Sep 10, 2020

Diagnostic Laboratory, Strasbourg University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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;