15-25356713-C-T

Position:

chr15-25356713-C-T

Variant summary

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

The NM_130839.5(UBE3A):c.1937G>A(p.Arg646His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,036 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

UBE3A
NM_130839.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 2.81

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:):

SNHG14 links:

Genome browser will be placed here

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 gene, where missense usually causes diseases (based on misZ statistic), UBE3A. . Trascript score misZ 6.9443 (greater than threshold 3.09). GenCC has associacion of gene with Angelman syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.2779091).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UBE3A	NM_130839.5 linkuse as main transcript	c.1937G>A	p.Arg646His	missense_variant	8/13	ENST00000648336.2	NP_570854.1	Q05086-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UBE3A	ENST00000648336.2 linkuse as main transcript	c.1937G>A	p.Arg646His	missense_variant	8/13		NM_130839.5	ENSP00000497572.2		Q05086-3

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152064

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251382

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135882

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1460972

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726832

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152064

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74254

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3476

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 18, 2019

The p.R626H variant (also known as c.1877G>A), located in coding exon 5 of the UBE3A gene, results from a G to A substitution at nucleotide position 1877. The arginine at codon 626 is replaced by histidine, an amino acid with highly similar properties. 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. -

Angelman syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 04, 2023

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 626 of the UBE3A protein (p.Arg626His). This variant is present in population databases (rs374601913, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with UBE3A-related conditions. ClinVar contains an entry for this variant (Variation ID: 1369495). 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 95%. 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 provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 13, 2023

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.072

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

Eigen

Benign

0.020

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.76

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

M_CAP

Benign

0.016

MetaRNN

Benign

0.28

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

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.34

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

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.26

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

REVEL

Benign

0.11

Sift

Benign

0.49

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

Sift4G

Benign

0.48

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

Polyphen

0.79, 0.64

.;P;.;.;.;P;.;P;.;P;.;.;.;.;P;.

Vest4

0.29, 0.27, 0.28, 0.28, 0.28, 0.27, 0.26, 0.27

MutPred

0.31

.;.;.;.;.;.;.;.;.;Gain of ubiquitination at K645 (P = 0.0599);.;.;.;.;Gain of ubiquitination at K645 (P = 0.0599);.;

MVP

0.48

MPC

1.1

ClinPred

0.21

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.41

gMVP

0.61

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over