15-25356713-C-G

Variant summary

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

The NM_130839.5(UBE3A):ā€‹c.1937G>Cā€‹(p.Arg646Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000014 ( 0 hom. )

Consequence

UBE3A
NM_130839.5 missense

Scores

6
13

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

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]
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 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=0.4008542).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
UBE3ANM_130839.5 linkc.1937G>C p.Arg646Pro missense_variant Exon 8 of 13 ENST00000648336.2 NP_570854.1 Q05086-3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
UBE3AENST00000648336.2 linkc.1937G>C p.Arg646Pro missense_variant Exon 8 of 13 NM_130839.5 ENSP00000497572.2 Q05086-3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1460972
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
726832
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
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.:
32
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1
Oct 16, 2015
Genetic Services Laboratory, University of Chicago
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Angelman syndrome Uncertain:1
May 20, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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 have shown that this missense change does not substantially affect UBE3A function (PMID: 33607653). 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. ClinVar contains an entry for this variant (Variation ID: 437193). This variant has not been reported in the literature in individuals affected with UBE3A-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 626 of the UBE3A protein (p.Arg626Pro). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.39
BayesDel_addAF
Uncertain
0.067
T
BayesDel_noAF
Benign
-0.14
CADD
Uncertain
24
DANN
Uncertain
0.98
DEOGEN2
Benign
0.11
.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;T
Eigen
Benign
-0.029
Eigen_PC
Benign
0.13
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Uncertain
0.88
.;.;.;D;.;.;.;D;.;.;.;.;D;D;D;D
M_CAP
Benign
0.023
T
MetaRNN
Benign
0.40
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.6
.;.;.;.;.;.;.;.;.;L;.;.;.;.;L;.
PrimateAI
Uncertain
0.58
T
PROVEAN
Benign
-1.3
.;.;.;.;N;.;.;.;.;.;.;N;N;.;N;.
REVEL
Benign
0.17
Sift
Benign
0.37
.;.;.;.;T;.;.;.;.;.;.;T;T;.;T;.
Sift4G
Benign
0.36
.;.;.;.;.;T;.;.;.;.;.;.;.;T;T;.
Polyphen
0.71, 0.0030
.;P;.;.;.;P;.;P;.;B;.;.;.;.;B;.
Vest4
0.59, 0.62, 0.59, 0.61, 0.59, 0.57, 0.60
MutPred
0.45
.;.;.;.;.;.;.;.;.;Loss of MoRF binding (P = 0.0465);.;.;.;.;Loss of MoRF binding (P = 0.0465);.;
MVP
0.46
MPC
1.3
ClinPred
0.77
D
GERP RS
4.8
Varity_R
0.85
gMVP
0.94

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.

Other links and lift over

dbSNP: rs374601913; hg19: chr15-25601860; API