rs587784527

chr15-25339185-CTCTT-Cchr15-25339185-CTCTT-CTCTTTCTT

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Strong PP5_Very_Strong

The NM_130839.5(UBE3A):c.2567_2570del(p.Lys856ArgfsTer4) variant causes a frameshift change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: UBE3A NM_130839.5 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:15 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 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 14 pathogenic variants in the truncated region.
• PP5: Variant 15-25339185-CTCTT-C is Pathogenic according to our data. Variant chr15-25339185-CTCTT-C is described in ClinVar as [Pathogenic]. Clinvar id is 160220.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr15-25339185-CTCTT-C is described in Lovd as [Likely_pathogenic]. Variant chr15-25339185-CTCTT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UBE3A	NM_130839.5	c.2567_2570del	p.Lys856ArgfsTer4	frameshift_variant	13/13	ENST00000648336.2
SNHG14	NR_146177.1	n.18393-52409_18393-52406del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UBE3A	ENST00000648336.2	c.2567_2570del	p.Lys856ArgfsTer4	frameshift_variant	13/13		NM_130839.5	P1
SNHG14	ENST00000656420.1	n.5456+60303_5456+60306del		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:15 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Angelman syndrome Pathogenic:9 Uncertain:1

Pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Apr 23, 2007	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Apr 04, 2024	- -
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	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Génétique des Maladies du Développement, Hospices Civils de Lyon	Apr 27, 2017	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 30, 2004	- -
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, 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	Invitae	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine	Feb 18, 2021	- -

not provided Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	- -
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) -

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;