rs139928148

Positions:

• chr15-25371359-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BS1 BS2 BP4

This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Asn272Ser variant in UBE3A is 0.013% in European (Non-Finnish) sub population in gnomAD, which is high enough to be classified as likely benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Asn272Ser variant is observed in at least 4 unaffected individuals (internal database) (BS2). Computational analysis prediction tools suggest that the p.Asn272Ser variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Asn272Ser variant in UBE3A is classified as benign based on the ACMG/AMP criteria (BS1, BS2, BP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA333443/MONDO:0007113/016

• Frequency:
  • Genomes: 𝑓 0.000098 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000099 (0 hom.)
• Consequence: UBE3A NM_130839.5 missense
• Clinical Significance: Benign reviewed by expert panel U:3 B:5
• Conservation: PhyloP100: 6.21

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UBE3A	NM_130839.5	c.815A>G	p.Asn272Ser	missense_variant	6/13	ENST00000648336.2
SNHG14	NR_146177.1	n.18393-20237T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UBE3A	ENST00000648336.2	c.815A>G	p.Asn272Ser	missense_variant	6/13		NM_130839.5	P1
SNHG14	ENST00000656420.1	n.5457-47429T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152204 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000103 AC: 26 AN: 251344 Hom.: 0 AF XY: 0.000110 AC XY: 15 AN XY: 135838

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000992 AC: 145 AN: 1461786 Hom.: 0 Cov.: 32 AF XY: 0.0000935 AC XY: 68 AN XY: 727188

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000103

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152322 Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6 AN XY: 74486

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000136 Hom.: 0

Bravo AF: 0.000166

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000173 AC: 21

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Uncertain:3 Benign:5

Revision: reviewed by expert panel

Submissions by phenotype

Angelman syndrome Uncertain:3 Benign:2

Benign, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Aug 25, 2022	The allele frequency of the p.Asn272Ser variant in UBE3A is 0.013% in European (Non-Finnish) sub population in gnomAD, which is high enough to be classified as likely benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Asn272Ser variant is observed in at least 4 unaffected individuals (internal database) (BS2). Computational analysis prediction tools suggest that the p.Asn272Ser variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Asn272Ser variant in UBE3A is classified as benign based on the ACMG/AMP criteria (BS1, BS2, BP4). -
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	Invitae	Jan 28, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 02, 2022

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. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 07, 2019

- -

UBE3A-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 22, 2020

This variant is classified as likely 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
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	18
DANN	Benign	0.88
Eigen	Benign	0.0028
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.072	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.54	T
Polyphen		0.57, 0.10	.;P;.;.;.;P;.;P;.;B;.;.;.;B;.
Vest4		0.14, 0.17, 0.12, 0.15, 0.12, 0.12, 0.15, 0.13
MVP		0.53
MPC		0.73
ClinPred		0.061	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.090
gMVP		0.21

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: rs139928148; hg19: chr15-25616506; COSMIC: COSV51669306; COSMIC: COSV51669306;