rs79328837

chr15-25355883-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_130839.5(UBE3A):c.2124+9T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00426 in 1,610,224 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• 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:10
• 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 15-25355883-A-G is Benign according to our data. Variant chr15-25355883-A-G is described in ClinVar as [Benign]. Clinvar id is 96260.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr15-25355883-A-G is described in Lovd as [Benign].
• BS2: High AC in GnomAd at 661 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UBE3A	NM_130839.5	c.2124+9T>C		intron_variant		ENST00000648336.2
SNHG14	NR_146177.1	n.18393-35713A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UBE3A	ENST00000648336.2	c.2124+9T>C		intron_variant			NM_130839.5	P1
SNHG14	ENST00000656420.1	n.5457-62905A>G		intron_variant, non_coding_transcript_variant

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:10

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 20, 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, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 28, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 22, 2017	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Angelman syndrome Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	- -
Benign, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Mar 26, 2021	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). -
Uncertain significance, no assertion criteria provided	clinical testing	Baylor Genetics	Feb 14, 2014	possible diagnosis of Angelman syndrome -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 27, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	SNHG14: BS2; UBE3A: BS2 -

UBE3A-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 09, 2019

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;