rs587783097

Positions:

• chr15-25339193-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2_Supporting PS4_Supporting PP1_Moderate PP3 PP4

This summary comes from the ClinGen Evidence Repository: The p.Leu835Phe variant in UBE3A is absent from gnomAD (PM2_Supporting). The p.Leu835Phe variant has been observed in at least 1 other affected individual (PMID 29655203) (PS4_Supporting). The variant has been reported to segregate in three informative meioses (PP1_moderate). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Leu835Phe variant in UBE3A has been reported in an individual with a clinical phenotype suggestive of Angelman syndrome (PP4). In summary, the p.Leu835Phe variant in UBE3A is classified as likely pathogenic for Angelman syndrome based on the ACMG/AMP criteria (PM2_supporting, PS4_supporting, PP1_moderate, PP3, PP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA294630/MONDO:0007113/016

• Frequency: Genomes: not found (cov: 32)
• Consequence: UBE3A NM_130839.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 U:2
• Conservation: PhyloP100: 10.0

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:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 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.
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UBE3A	NM_130839.5	c.2563C>T	p.Leu855Phe	missense_variant	13/13	ENST00000648336.2	NP_570854.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UBE3A	ENST00000648336.2	c.2563C>T	p.Leu855Phe	missense_variant	13/13		NM_130839.5	ENSP00000497572.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Angelman syndrome Pathogenic:2

Likely pathogenic, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Mar 26, 2021	The p.Leu835Phe variant in UBE3A is absent from gnomAD (PM2_Supporting). The p.Leu835Phe variant has been observed in at least 1 other affected individual (PMID 29655203) (PS4_Supporting). The variant has been reported to segregate in three informative meioses (PP1_moderate). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Leu835Phe variant in UBE3A has been reported in an individual with a clinical phenotype suggestive of Angelman syndrome (PP4). In summary, the p.Leu835Phe variant in UBE3A is classified as likely pathogenic for Angelman syndrome based on the ACMG/AMP criteria (PM2_supporting, PS4_supporting, PP1_moderate, PP3, PP4). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

See cases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Jun 24, 2022

ACMG categories: PM2 -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 28, 2013

.Leu855Phe (CTT>TTT): c.2563 C>T in exon 13 of the UBE3A gene (NM_130839.1) The novel Leu855Phe missense change has not been published as pathogenic, nor has it been reported as a benign polymorphism to our knowledge. An external variant database has not identifiedLeu855Phe in approximately 6,500 individuals of European or African American ethnicity, indicating that it is not a common benign variant in these populations. The amino acid substitution is conservative, as Leucine and Phenylalanine are both uncharged, non-polar amino acids. However, it alters a highly conserved position in the HECT domain of the protein where multiple other missense variants have been reported in association with Angelman syndrome, and multiple in silico algorithms predict it may be damaging to protein structure/function. Therefore, based on the currently available information, Leu855Phe is a strong candidate for a pathogenic variant, although the possibility that it is a benign variant cannot be excluded. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.24	T;.;.;.;.;.;.;.;.;T;.;.;.;.;T
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;.;.;.;.;.;.;D;.;.;.;.;D;D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Uncertain	2.9	.;.;.;.;.;.;.;.;.;M;.;.;.;.;M
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.9	.;.;.;.;D;.;.;.;.;.;.;D;D;.;D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	.;.;.;.;D;.;.;.;.;.;.;D;D;.;D
Sift4G	Pathogenic	0.0	.;.;.;.;.;D;.;.;.;.;.;.;.;D;D
Polyphen		1.0	.;.;D;.;.;D;.;D;.;D;.;.;.;.;D
Vest4		0.84, 0.65, 0.79, 0.64, 0.86, 0.86, 0.84
MutPred		0.86		.;.;.;.;.;.;.;.;.;Gain of methylation at K859 (P = 0.0296);.;.;.;.;Gain of methylation at K859 (P = 0.0296);
MVP		0.88
MPC		2.1
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.97

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: rs587783097; hg19: chr15-25584340;