rs772952625
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate
The NM_130839.5(UBE3A):c.278A>C(p.Tyr93Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 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: 6.8e-7 ( 0 hom. )
Consequence
UBE3A
NM_130839.5 missense
NM_130839.5 missense
Scores
1
1
10
Clinical Significance
Conservation
PhyloP100: 4.58
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, UBE3A
BP4
?
Computational evidence support a benign effect (MetaRNN=0.18981346).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
UBE3A | NM_130839.5 | c.278A>C | p.Tyr93Ser | missense_variant | 5/13 | ENST00000648336.2 | |
SNHG14 | NR_146177.1 | n.18393-16048T>G | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
UBE3A | ENST00000648336.2 | c.278A>C | p.Tyr93Ser | missense_variant | 5/13 | NM_130839.5 | P1 | ||
SNHG14 | ENST00000656420.1 | n.5457-43240T>G | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
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32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251390Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135884
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461882Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 727240
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GnomAD4 genome ? Cov.: 32
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32
ExAC
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Angelman syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 22, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 20, 2023 | ClinVar contains an entry for this variant (Variation ID: 521156). This sequence change replaces tyrosine, which is neutral and polar, with serine, which is neutral and polar, at codon 73 of the UBE3A protein (p.Tyr73Ser). This variant is present in population databases (rs772952625, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with UBE3A-related conditions. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on UBE3A protein function. 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. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 28, 2016 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Uncertain
T
Polyphen
0.0030, 0.0020
.;B;.;.;.;B;.;B;.;B;.;.;.;B;.;.;.
Vest4
0.59, 0.57, 0.56, 0.56, 0.55, 0.66, 0.58
MutPred
0.32
.;.;.;.;.;.;.;.;.;Loss of helix (P = 0.0196);.;.;.;Loss of helix (P = 0.0196);.;.;.;
MVP
0.39
MPC
1.3
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at