rs1064794579

Positions:

• chr15-25371315-C-T

Variant summary

Our verdict is Uncertain significance. Variant got -1 ACMG points: 0P and 1B. BP4

This summary comes from the ClinGen Evidence Repository: The p.Val267Ile variant in UBE3A is present in one individual in gnomAD (does not meet PM2_supporting or BS1). Computational analysis prediction tools suggests that the p.Val267Ile variant in UBE3A does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Val267Ile variant in UBE3A is classified as a Variant of Uncertain Significance based on the ACMG/AMP criteria (BP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA16619910/MONDO:0007113/016

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: UBE3A NM_130839.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:3
• Conservation: PhyloP100: 4.12

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 -1 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UBE3A	NM_130839.5	c.859G>A	p.Val287Ile	missense_variant	6/13	ENST00000648336.2
SNHG14	NR_146177.1	n.18393-20281C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UBE3A	ENST00000648336.2	c.859G>A	p.Val287Ile	missense_variant	6/13		NM_130839.5	P1
SNHG14	ENST00000656420.1	n.5457-47473C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251138 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135770

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461836 Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6 AN XY: 727218

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: 0.00000630

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: reviewed by expert panel

Submissions by phenotype

Angelman syndrome Uncertain:2

Uncertain significance, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Apr 02, 2021	The p.Val267Ile variant in UBE3A is present in one individual in gnomAD (does not meet PM2_supporting or BS1). Computational analysis prediction tools suggests that the p.Val267Ile variant in UBE3A does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Val267Ile variant in UBE3A is classified as a Variant of Uncertain Significance based on the ACMG/AMP criteria (BP4). -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 10, 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. 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. ClinVar contains an entry for this variant (Variation ID: 420601). This variant has not been reported in the literature in individuals affected with UBE3A-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 267 of the UBE3A protein (p.Val267Ile). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 22, 2017

A variant of uncertain significance has been identified in the UBE3A gene. The V267I variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The V267I variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The V267I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Valine are tolerated across species, and Isoleucine has been seen at this position in evolution. However, a missense variant in a nearby residue (L263W) has been reported in the Human Gene Mutation Database in association with Angelman syndrome (Stenson et al., 2014). In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.11	.;.;.;.;.;.;.;.;.;T;.;.;.;T;T
Eigen	Benign	0.041
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	.;.;.;D;.;.;.;D;.;.;.;.;D;D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.16	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	.;.;.;.;.;.;.;.;.;L;.;.;.;L;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.31	.;.;.;.;N;.;.;.;.;.;.;N;N;N;.
REVEL	Benign	0.090
Sift	Benign	0.53	.;.;.;.;T;.;.;.;.;.;.;T;T;T;.
Sift4G	Benign	0.77	.;.;.;.;.;T;.;.;.;.;.;.;.;T;.
Polyphen		0.45, 0.0040	.;B;.;.;.;B;.;B;.;B;.;.;.;B;.
Vest4		0.13, 0.13, 0.10, 0.12, 0.10, 0.10, 0.094
MutPred		0.40		.;.;.;.;.;.;.;.;.;Loss of catalytic residue at V290 (P = 0.0261);.;.;.;Loss of catalytic residue at V290 (P = 0.0261);.;
MVP		0.24
MPC		0.75
ClinPred		0.30	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.070
gMVP		0.36

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: rs1064794579; hg19: chr15-25616462;