rs139082033

Positions:

chr15-25356883-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The allele frequency of the c.1707C>T p.(Tyr569=) variant in UBE3A (NM_130838.2) is 0.15% in the European (non-Finnish) sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). In summary, the c.1707C>T p.(Tyr569=) variant in UBE3A is classified as Benign based on the ACMG/AMP criteria (BA1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA205044/MONDO:0007113/016

Frequency

Genomes: 𝑓 0.00092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 6 hom. )

Consequence

UBE3A
NM_130839.5 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:11

Conservation

PhyloP100: 1.69

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]

UBE3A links:

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]

SNHG14 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BA1

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 linkuse as main transcript	c.1767C>T	p.Tyr589=	synonymous_variant	8/13	ENST00000648336.2	NP_570854.1
SNHG14	NR_146177.1 linkuse as main transcript	n.18393-34713G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UBE3A	ENST00000648336.2 linkuse as main transcript	c.1767C>T	p.Tyr589=	synonymous_variant	8/13		NM_130839.5	ENSP00000497572	P1	Q05086-3
SNHG14	ENST00000656420.1 linkuse as main transcript	n.5457-61905G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.000927

AC:

141

AN:

152070

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00188

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000781

AC:

196

AN:

251006

Hom.:

AF XY:

0.000825

AC XY:

112

AN XY:

135790

show subpopulations

Gnomad AFR exome

AF:

0.000434

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00154

Gnomad OTH exome

AF:

0.000655

GnomAD4 exome

AF:

0.00165

AC:

2404

AN:

1460800

Hom.:

Cov.:

AF XY:

0.00158

AC XY:

1148

AN XY:

726742

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.000335

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.0000937

Gnomad4 NFE exome

AF:

0.00208

Gnomad4 OTH exome

AF:

0.00104

GnomAD4 genome

AF:

0.000920

AC:

140

AN:

152188

Hom.:

Cov.:

AF XY:

0.000766

AC XY:

AN XY:

74414

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00187

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00155

Hom.:

Bravo

AF:

0.000948

EpiCase

AF:

0.00142

EpiControl

AF:

0.00119

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:11

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 05, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 12, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 10, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Angelman syndrome

Uncertain:1Benign:2

Uncertain significance, no assertion criteria provided	clinical testing	Baylor Genetics	Feb 14, 2014	possible diagnosis of Angelman syndrome -
Benign, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Jun 30, 2022	The allele frequency of the c.1707C>T p.(Tyr569=) variant in UBE3A (NM_130838.2) is 0.15% in the European (non-Finnish) sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). In summary, the c.1707C>T p.(Tyr569=) variant in UBE3A is classified as Benign based on the ACMG/AMP criteria (BA1). -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not provided

Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	UBE3A: BP4, BP7, BS1 -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 25, 2017

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

CADD

Benign

7.3

DANN

Benign

0.52

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over