rs587781234

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PP4PS4_SupportingPM6_StrongPM2_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

Scores

Not classified

Clinical Significance

Likely pathogenic reviewed by expert panel P:4

Conservation

PhyloP100: 10.0
Variant links:
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]

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ACMG classification

Classification made for transcript

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
UBE3ANM_130839.5 linkc.1805_1807delCTT p.Ser602del disruptive_inframe_deletion 8/13 ENST00000648336.2 NP_570854.1 Q05086-3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
UBE3AENST00000648336.2 linkc.1805_1807delCTT p.Ser602del disruptive_inframe_deletion 8/13 NM_130839.5 ENSP00000497572.2 Q05086-3

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
LINK: link

Submissions by phenotype

Angelman syndrome Pathogenic:4
Likely pathogenic, reviewed by expert panelcurationClinGen Rett and Angelman-like Disorders Variant Curation Expert PanelMar 26, 2021The 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 submitterclinical testingGenetic Services Laboratory, University of ChicagoJun 27, 2019- -
Pathogenic, no assertion criteria providedclinical testingBaylor GeneticsFeb 14, 2014- -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 20, 2019Experimental 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

Name
Calibrated prediction
Score
Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs587781234; hg19: chr15-25601989; API