rs1064793307

Variant names:

• chr15-25370598-G-A
• rs1064793307
• NM_130839.5:c.1576C>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PS4 PS3_Supporting PM6 PP3 PP4 PP1 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1576C>T (p.Arg526Cys) variant in the UBE3A gene has been observed in at least 5 individuals with Angelman syndrome (PMID:10647895, 19213023, 23708187, 25212744; GeneDx: internal database) (PS4). The p.Arg526Cys variant in UBE3A has been reported as an unconfirmed de novo occurrence in a individual with Angelman syndrome (PMID:10647895) (PM6). The variant has been reported to segregate in two informative meioses (PMID:23708187) (PP1). The computational predictor REVEL gives a score of 0.866, which is above the threshold of 0.644, evidence that correlates with impact to UBE3A function (PP3). The p.Arg526Cys variant in UBE3A has been reported in an individual with a clinical phenotype suggestive of Angelman syndrome (PMID:10647895) (PP4). The p.Arg526Cys variant in UBE3A is absent from gnomAD v4.1 (PM2_Supporting). Protein expression analysis in transfected cell lines has shown that this variant destabilizes the protein, demonstrated by significantly reduced protein levels (PMID:26255772) (PS3_Supporting). In summary, the p.Arg526Cys variant in UBE3A is classified as Pathogenic for Angelman syndrome based on the ACMG/AMP criteria (PS4, PM6, PP1, PP3, PP4, PM2_supporting, PS3_supporting) (UBE3A specifications version 5.0; curation approved on 2/28/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA16619907/MONDO:0007113/037

• Frequency: Genomes: not found (cov: 32)
• Consequence: UBE3A NM_000462.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 4.30
• Publications: 9 publications found

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

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PS3: 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.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000462.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBE3A	NM_130839.5	MANE Select	c.1576C>T	p.Arg526Cys	missense	Exon 6 of 13	NP_570854.1
	UBE3A	NM_000462.5		c.1585C>T	p.Arg529Cys	missense	Exon 7 of 14	NP_000453.2
	UBE3A	NM_001354505.1		c.1576C>T	p.Arg526Cys	missense	Exon 6 of 13	NP_001341434.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBE3A	ENST00000648336.2	MANE Select	c.1576C>T	p.Arg526Cys	missense	Exon 6 of 13	ENSP00000497572.2
	UBE3A	ENST00000566215.5	TSL:1	c.1516C>T	p.Arg506Cys	missense	Exon 8 of 15	ENSP00000457771.1
	SNHG14	ENST00000424333.6	TSL:1	n.5767-48190G>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	Angelman syndrome (3)
2	-	-	not provided (2)
1	-	-	UBE3A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Uncertain	0.72	D
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.6	H
PhyloP100		4.3
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-8.0	D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.92		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
Mutation Taster		=2/98	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1064793307; hg19: chr15-25615745; COSMIC: COSV51660557; COSMIC: COSV51660557;