15-25340164-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PP2 PP3_Moderate

The NM_130839.5(UBE3A):c.2419A>G(p.Thr807Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T807M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: UBE3A NM_130839.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:6 B:1
• Conservation: PhyloP100: 8.02

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a domain HECT (size 99) in uniprot entity UBE3A_HUMAN there are 16 pathogenic changes around while only 1 benign (94%) in NM_130839.5
• PP2: Missense variant where missense usually causes diseases, UBE3A
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.938

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UBE3A	NM_130839.5	c.2419A>G	p.Thr807Ala	missense_variant	12/13	ENST00000648336.2
SNHG14	NR_146177.1	n.18393-51432T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UBE3A	ENST00000648336.2	c.2419A>G	p.Thr807Ala	missense_variant	12/13		NM_130839.5	P1
SNHG14	ENST00000656420.1	n.5456+61280T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461774 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727182

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000189

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

Angelman syndrome Uncertain:3

Uncertain significance, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Jun 20, 2023	The c.2359A>G p.Thr787Ala variant in UBE3A (NM_130838.2) is absent from gnomAD (PM2_Supporting). The p.Thr787Ala variant has been observed in multiple individuals with seizures, where at least 2 of these cases are known to be maternally inherited (Invitae internal data) (PS4_Supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). Functional studies suggest p.Thr787Ala is a gain of function variant that increases UBE3A ubiquitin ligase activity (PMID: 34815418). However, as loss of function is the known mechanism of UBE3A-associated disease, this evidence has not been applied. In summary, the p.Thr787Ala variant in UBE3A is classified as a Variant of Uncertain Significance based on the ACMG/AMP criteria (PM2_Supporting, PS4_Supporting, PP3). -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jul 20, 2023	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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on UBE3A function (PMID: 34815418). 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 expected to disrupt UBE3A protein function. ClinVar contains an entry for this variant (Variation ID: 418562). This missense change has been observed in individual(s) with clinical features of UBE3A-related conditions (PMID: 34815418). This variant is present in population databases (rs374519603, gnomAD 0.0009%). This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 787 of the UBE3A protein (p.Thr787Ala). -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 22, 2023	- -

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 05, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 24, 2023	Published functional studies demonstrate that this variant increases UBE3A activity and accelerates ubiquitination activity (Weston et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26219744, 25884337, 25212744, 22670133, 19213023, 17940072, 17765640, 15263005, 8988171, 2309781, 34815418) -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 07, 2017

Lines of evidence used in support of classification: UNCERTAIN: Alteration(s) of Uncertain Clinical Significance Detected -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
Cadd	Pathogenic	28
Dann	Uncertain	1.0
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.81	D
Polyphen		0.98, 1.0	.;D;.;.;.;D;.;D;.;D;.;.;.;.;D
Vest4		0.90, 0.65, 0.90, 0.94
MVP		0.95
MPC		2.0
ClinPred		0.99	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.86
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs374519603; hg19: chr15-25585311;