rs1064793307

chr15-25370598-G-A

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_130839.5(UBE3A):c.1576C>T(p.Arg526Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R526H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: UBE3A NM_130839.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 4.30

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 19 ACMG points.

• PM1: In a strand (size 2) in uniprot entity UBE3A_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_130839.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-25370597-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 421257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, UBE3A
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 15-25370598-G-A is Pathogenic according to our data. Variant chr15-25370598-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 418572.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr15-25370598-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UBE3A	NM_130839.5	c.1576C>T	p.Arg526Cys	missense_variant	6/13	ENST00000648336.2
SNHG14	NR_146177.1	n.18393-20998G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UBE3A	ENST00000648336.2	c.1576C>T	p.Arg526Cys	missense_variant	6/13		NM_130839.5	P1
SNHG14	ENST00000656420.1	n.5457-48190G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

Submissions by phenotype

Angelman syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jan 21, 2021	This sequence change replaces arginine with cysteine at codon 506 of the UBE3A protein (p.Arg506Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to be de novo in an individual affected with Angelman syndrome (PMID: 26255772). This variant has also been reported to be maternally inherited in an unrelated individual affected with Angelman syndrome (PMID: 19213023). ClinVar contains an entry for this variant (Variation ID: 418572). Experimental studies have shown that this missense change results in reduced UBE3A protein expression (PMID: 26255772). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Mar 25, 2021	The c.1516C>T (p.Arg506Cys) variant in UBE3A is absent from gnomAD (PM2_supporting). This variant has been observed in at least 3 individuals with Angelman syndrome (PMID 10647895, 19213023, 23708187) (PS4_moderate). The p.Arg506Cys variant in UBE3A has been reported as an unconfirmed de novo occurrence in an individual with Angelman syndrome (PMID 10647895) (PM6). The variant has been reported to segregate in two informative meioses (PMID 23708187) (PP1). Protein expression analysis in transfected cell lines has shown that this variant impacts protein function (PMID: 26255772) (PS3_supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Arg506Cys variant in UBE3A is classified as likely pathogenic for Angelman syndrome based on the ACMG/AMP criteria (PS4_moderate, PM6, PS3_supporting, PM2_supporting, PP1, PP3, PP4). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 15, 2018	This sequence change replaces arginine with cysteine at codon 506 of the UBE3A protein (p.Arg506Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to be de novo in an individual affected with Angelman syndrome (PMID: 26255772). This variant has also been reported to be maternally inherited in an unrelated individual affected with Angelman syndrome (PMID: 19213023). ClinVar contains an entry for this variant (Variation ID: 418572). Experimental studies have shown that this missense change results in reduced UBE3A protein expression (PMID: 26255772). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 17, 2017	The R506C variant in the UBE3A gene has been reported previously in association with Angelman syndrome (Baumer et al., 1999; Camprubi et al., 2009; Carvill et al., 2013; Yi et al., 2015). The R506C variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R506C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R506C as a pathogenic variant. -

UBE3A-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 10, 2024

The UBE3A c.1516C>T variant is predicted to result in the amino acid substitution p.Arg506Cys. This variant has been reported as maternally-inherited or de novo in individuals with Angelman syndrome (Baumer et al. 1999. PubMed ID: 10647895; Table S2, Truty et al. 2019. PubMed ID: 31440721; Table S1, Du et al. 2022. PubMed ID: 36011358). This variant has not been reported in a large population database, indicating this variant is rare. Given the evidence, we interpret this variant as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.94	D
Polyphen		1.0	.;D;.;.;.;D;.;D;.;D;.;.;.;D;.
Vest4		0.98, 0.89, 0.96, 0.88, 0.96, 0.96
MutPred		0.92		.;.;.;.;.;.;.;.;.;Loss of catalytic residue at R529 (P = 0.0445);.;.;.;Loss of catalytic residue at R529 (P = 0.0445);.;
MVP		0.97
MPC		2.4
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.88
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs1064793307; hg19: chr15-25615745; COSMIC: COSV51660557; COSMIC: COSV51660557;