15-25354363-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received -1 ACMG points: 0P and 1B. BP4

This summary comes from the ClinGen Evidence Repository: The c.2284G>A p.(Val762Ile) variant in UBE3A (NM_130838.2) is present in gnomAD v2.1.1 at a frequency of 0.004% in the African/African-American sub population (no criteria met). The p.(Val762Ile) variant has been observed in at least 1 individual with a neurodevelopmental phenotype consistent with UBE3A-related disease (PMID 25212744), however the PS4 criteria cannot be applied due to the gnomAD frequency of this variant. Computational analysis prediction tools suggest that the p.(Val762Ile) variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the c.2284G>A p.(Val762Ile) variant in UBE3A is classified as a Variant of Uncertain Signficance based on the ACMG/AMP criteria (BP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA173814/MONDO:0007113/016

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000050 ( 0 hom. )

Consequence

UBE3A
NM_130839.5 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:4B:2

Conservation

PhyloP100: 4.12

Publications

3 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received -1 ACMG points.

BP4

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 link	c.2344G>A	p.Val782Ile	missense_variant	Exon 11 of 13	ENST00000648336.2	NP_570854.1	Q05086-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UBE3A	ENST00000648336.2 link	c.2344G>A	p.Val782Ile	missense_variant	Exon 11 of 13		NM_130839.5	ENSP00000497572.2		Q05086-3

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000119

AC:

AN:

251316

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000500

AC:

AN:

1461140

Hom.:

Cov.:

AF XY:

0.0000454

AC XY:

AN XY:

726896

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33452

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39662

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86228

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5352

European-Non Finnish (NFE)

AF:

0.0000639

AC:

AN:

1111876

Other (OTH)

AF:

0.0000166

AC:

AN:

60316

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41446

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000557

Hom.:

Bravo

AF:

0.0000189

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4Benign:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Angelman syndrome

Uncertain:3

Jun 30, 2022

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance:Uncertain significance

Review Status:reviewed by expert panel

Collection Method:curation

The c.2284G>A p.(Val762Ile) variant in UBE3A (NM_130838.2) is present in gnomAD v2.1.1 at a frequency of 0.004% in the African/African-American sub population (no criteria met). The p.(Val762Ile) variant has been observed in at least 1 individual with a neurodevelopmental phenotype consistent with UBE3A-related disease (PMID 25212744), however the PS4 criteria cannot be applied due to the gnomAD frequency of this variant. Computational analysis prediction tools suggest that the p.(Val762Ile) variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the c.2284G>A p.(Val762Ile) variant in UBE3A is classified as a Variant of Uncertain Signficance based on the ACMG/AMP criteria (BP4). -

Feb 14, 2014

Baylor Genetics

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

possible diagnosis of Angelman syndrome -

Dec 21, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 762 of the UBE3A protein (p.Val762Ile). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of Angelman syndrome (PMID: 25212744). ClinVar contains an entry for this variant (Variation ID: 156124). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt UBE3A protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Benign:2

May 08, 2015

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 01, 2016

GeneDx

Significance:Likely 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. -

Inborn genetic diseases

Uncertain:1

Jun 21, 2017

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.V762I variant (also known as c.2284G>A), located in coding exon 8 of the UBE3A gene, results from a G to A substitution at nucleotide position 2284. The valine at codon 762 is replaced by isoleucine, an amino acid with highly similar properties. This alteration has been detected in a proband from an Angelman syndrome cohort and in the proband's reportedly symptomatic maternal half-sibling; however, clinical details were limited (Sadikovic B et al. Hum. Mutat., 2014 Dec;35:1407-17). 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

0.063

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.12

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

Eigen

Benign

-0.20

Eigen_PC

Benign

0.039

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.77

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

M_CAP

Benign

0.0075

MetaRNN

Benign

0.18

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.59

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

PhyloP100

4.1

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.95

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

REVEL

Benign

0.050

Sift

Benign

0.17

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

Sift4G

Benign

0.13

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

Polyphen

0.0, 0.0030

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

Vest4

0.23, 0.25, 0.24, 0.24, 0.24, 0.23, 0.086

MutPred

0.44

.;.;.;.;.;.;.;.;.;Loss of helix (P = 0.1299);.;.;.;.;Loss of helix (P = 0.1299);.;

MVP

0.23

MPC

0.75

ClinPred

0.25

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.16

gMVP

0.32

Mutation Taster

=91/9

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over