rs374519603

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP2PP3_Strong

The NM_130839.5(UBE3A):​c.2419A>T​(p.Thr807Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Consequence

UBE3A
NM_130839.5 missense

Scores

9
5
5

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.02
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 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.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.978

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
UBE3ANM_130839.5 linkuse as main transcriptc.2419A>T p.Thr807Ser missense_variant 12/13 ENST00000648336.2 NP_570854.1 Q05086-3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
UBE3AENST00000648336.2 linkuse as main transcriptc.2419A>T p.Thr807Ser missense_variant 12/13 NM_130839.5 ENSP00000497572.2 Q05086-3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.95
BayesDel_addAF
Pathogenic
0.19
D
BayesDel_noAF
Uncertain
0.030
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.34
.;.;.;.;.;.;.;.;.;T;.;.;.;.;T
Eigen
Pathogenic
0.70
Eigen_PC
Pathogenic
0.70
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.80
.;.;.;T;.;.;.;D;.;.;.;.;D;D;D
M_CAP
Uncertain
0.19
D
MetaRNN
Pathogenic
0.98
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
0.89
D
MutationAssessor
Uncertain
2.6
.;.;.;.;.;.;.;.;.;M;.;.;.;.;M
PrimateAI
Pathogenic
0.82
D
PROVEAN
Uncertain
-3.4
.;.;.;.;D;.;.;.;.;.;.;D;D;.;D
REVEL
Pathogenic
0.79
Sift
Benign
0.044
.;.;.;.;D;.;.;.;.;.;.;D;D;.;D
Sift4G
Benign
0.094
.;.;.;.;.;T;.;.;.;.;.;.;.;T;T
Polyphen
0.74, 0.99
.;P;.;.;.;P;.;P;.;D;.;.;.;.;D
Vest4
0.57, 0.38, 0.56, 0.57, 0.57, 0.66
MutPred
0.97
.;.;.;.;.;.;.;.;.;Gain of disorder (P = 0.1185);.;.;.;.;Gain of disorder (P = 0.1185);
MVP
0.82
MPC
1.9
ClinPred
0.98
D
GERP RS
5.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.78
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: rs374519603; hg19: chr15-25585311; COSMIC: COSV51665631; COSMIC: COSV51665631; API