rs587782910

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_130839.5(UBE3A):c.2344G>T(p.Val782Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

UBE3A
NM_130839.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.12

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the UBE3A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 44 curated pathogenic missense variants (we use a threshold of 10). The gene has 8 curated benign missense variants. Trascript score misZ: 6.9443 (above the threshold of 3.09). GenCC associations: The gene is linked to Angelman syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.3059991).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UBE3A	NM_130839.5 link	c.2344G>T	p.Val782Phe	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>T	p.Val782Phe	missense_variant	Exon 11 of 13		NM_130839.5	ENSP00000497572.2		Q05086-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461142

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726896

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Angelman syndrome

Uncertain:1

Nov 04, 2024

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 phenylalanine, which is neutral and non-polar, at codon 762 of the UBE3A protein (p.Val762Phe). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with UBE3A-related conditions. Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.058

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

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

Eigen

Benign

-0.064

Eigen_PC

Benign

0.13

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

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

M_CAP

Benign

0.017

MetaRNN

Benign

0.31

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

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.34

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

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.5

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

REVEL

Benign

0.039

Sift

Benign

0.049

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

Sift4G

Uncertain

0.034

.;.;.;.;.;D;.;.;.;.;.;.;.;T;D;.

Polyphen

0.0060, 0.14

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

Vest4

0.46, 0.49, 0.50, 0.49, 0.49, 0.48, 0.21

MutPred

0.40

.;.;.;.;.;.;.;.;.;Loss of disorder (P = 0.2452);.;.;.;.;Loss of disorder (P = 0.2452);.;

MVP

0.26

MPC

1.2

ClinPred

0.84

GERP RS

4.6

Varity_R

0.30

gMVP

0.64

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over