rs141984760

Positions:

chr15-25371110-C-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BA1BP4

This summary comes from the ClinGen Evidence Repository: The allele frequency of the c.1064G>C p.(Ser355Thr) variant in UBE3A (NM_130839.5) is 0.078% in the South Asian 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.1064G>C p.(Ser355Thr) variant in UBE3A is classified as Benign based on the ACMG/AMP criteria (BA1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA333425/MONDO:0007113/016

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000088 ( 2 hom. )

Consequence

UBE3A
NM_130839.5 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:3B:3

Conservation

PhyloP100: 0.458

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 -9 ACMG points.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

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.1064G>C	p.Ser355Thr	missense_variant	6/13	ENST00000648336.2	NP_570854.1
SNHG14	NR_146177.1 linkuse as main transcript	n.18393-20486C>G		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.1064G>C	p.Ser355Thr	missense_variant	6/13		NM_130839.5	ENSP00000497572	P1	Q05086-3
SNHG14	ENST00000656420.1 linkuse as main transcript	n.5457-47678C>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0000788

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.000143

AC:

AN:

251254

Hom.:

AF XY:

0.000191

AC XY:

AN XY:

135794

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000785

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000792

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000876

AC:

128

AN:

1461820

Hom.:

Cov.:

AF XY:

0.000110

AC XY:

AN XY:

727192

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000870

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000297

Gnomad4 OTH exome

AF:

0.0000993

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152310

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00103

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.0000675

Hom.:

Bravo

AF:

0.0000567

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000173

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Benign

Submissions summary: Uncertain:3Benign:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Angelman syndrome

Uncertain:1Benign:2

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.1064G>C p.(Ser355Thr) variant in UBE3A (NM_130839.5) is 0.078% in the South Asian 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.1064G>C p.(Ser355Thr) variant in UBE3A is classified as Benign based on the ACMG/AMP criteria (BA1). -
Uncertain significance, no assertion criteria provided	clinical testing	Baylor Genetics	Feb 14, 2014	possible diagnosis of Angelman syndrome -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 06, 2023	- -

not provided

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2021	This variant is associated with the following publications: (PMID: 25212744) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2016	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 15, 2017

The p.S335T variant (also known as c.1004G>C), located in coding exon 3 of the UBE3A gene, results from a G to C substitution at nucleotide position 1004. The serine at codon 335 is replaced by threonine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.71

CADD

Benign

DANN

Benign

0.78

DEOGEN2

Benign

0.13

.;.;.;.;.;.;.;.;.;T;.;.;.;T;T

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.28

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.90

.;.;.;D;.;.;.;D;.;.;.;.;D;D;D

M_CAP

Benign

0.0073

MetaRNN

Benign

0.020

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

.;.;.;.;.;.;.;.;.;L;.;.;.;L;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.060

.;.;.;.;N;.;.;.;.;.;.;N;N;N;.

REVEL

Benign

0.13

Sift

Benign

0.75

.;.;.;.;T;.;.;.;.;.;.;T;T;T;.

Sift4G

Benign

0.58

.;.;.;.;.;T;.;.;.;.;.;.;.;T;.

Polyphen

0.018, 0.031

.;B;.;.;.;B;.;B;.;B;.;.;.;B;.

Vest4

0.19, 0.15, 0.13, 0.17, 0.13, 0.14, 0.15, 0.12

MVP

0.34

MPC

0.84

ClinPred

0.015

GERP RS

2.6

Varity_R

0.11

gMVP

0.29

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