rs79328837

Variant names:

• chr15-25355883-A-G
• rs79328837
• NM_130839.5:c.2124+9T>C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BA1 BP4

This summary comes from the ClinGen Evidence Repository: The allele frequency of the c.2064+9T>C variant in UBE3A is 0.4% 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. Splice prediction analysis, using multiple computational tools does not suggest an impact to splicing (BP4). In summary, the c.2064+9T>C variant in UBE3A is classified as benign based on the ACMG/AMP criteria (BA1, BP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA149405/MONDO:0007113/016

• Frequency:
  • Genomes: 𝑓 0.0044 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (21 hom.)
• Consequence: UBE3A NM_130839.5 intron
• Clinical Significance: Benign reviewed by expert panel U:1 B:11
• Conservation: PhyloP100: 0.286

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 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 rank	MANE	Protein	UniProt
UBE3A	NM_130839.5	c.2124+9T>C		intron_variant	Intron 9 of 12	ENST00000648336.2	NP_570854.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UBE3A	ENST00000648336.2	c.2124+9T>C		intron_variant	Intron 9 of 12		NM_130839.5	ENSP00000497572.2

Frequencies

GnomAD3 genomes AF: 0.00434 AC: 661 AN: 152170 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0102

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00811

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00513

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00442 AC: 1108 AN: 250526 Hom.: 2 AF XY: 0.00443 AC XY: 600 AN XY: 135448

Gnomad AFR exome AF: 0.000556

Gnomad AMR exome AF: 0.00663

Gnomad ASJ exome AF: 0.00577

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.00699

Gnomad NFE exome AF: 0.00544

Gnomad OTH exome AF: 0.00541

GnomAD4 exome AF: 0.00425 AC: 6190 AN: 1457940 Hom.: 21 Cov.: 31 AF XY: 0.00420 AC XY: 3044 AN XY: 725522

Gnomad4 AFR exome AF: 0.00102

Gnomad4 AMR exome AF: 0.00647

Gnomad4 ASJ exome AF: 0.00510

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000314

Gnomad4 FIN exome AF: 0.00736

Gnomad4 NFE exome AF: 0.00449

Gnomad4 OTH exome AF: 0.00477

GnomAD4 genome AF: 0.00437 AC: 665 AN: 152284 Hom.: 2 Cov.: 32 AF XY: 0.00481 AC XY: 358 AN XY: 74462

Gnomad4 AFR AF: 0.000794

Gnomad4 AMR AF: 0.0102

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00811

Gnomad4 NFE AF: 0.00515

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00427 Hom.: 1

Bravo AF: 0.00417

EpiCase AF: 0.00627

EpiControl AF: 0.00683

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:11

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:6

Jun 20, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 04, 2024

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 22, 2017

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 28, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Angelman syndrome Uncertain:1 Benign:2

Mar 26, 2021

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The allele frequency of the c.2064+9T>C variant in UBE3A is 0.4% 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. Splice prediction analysis, using multiple computational tools does not suggest an impact to splicing (BP4). In summary, the c.2064+9T>C variant in UBE3A is classified as benign based on the ACMG/AMP criteria (BA1, BP4). -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 14, 2014

Baylor Genetics

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

possible diagnosis of Angelman syndrome -

not provided Benign:2

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

UBE3A: BS2 -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

UBE3A-related disorder Benign:1

May 09, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	6.3
DANN	Benign	0.75

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: rs79328837; hg19: chr15-25601030;