rs1555393242

Positions:

• chr15-25360440-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PP2 PP3_Strong PP5_Moderate

The NM_130839.5(UBE3A):​c.1696G>A​(p.Gly566Ser) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: UBE3A NM_130839.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.91

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:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 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, 0.954
• PP5: Variant 15-25360440-C-T is Pathogenic according to our data. Variant chr15-25360440-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 559871.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UBE3A	NM_130839.5	c.1696G>A	p.Gly566Ser	missense_variant	7/13	ENST00000648336.2	NP_570854.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UBE3A	ENST00000648336.2	c.1696G>A	p.Gly566Ser	missense_variant	7/13		NM_130839.5	ENSP00000497572.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Angelman syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Aug 11, 2017

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	.;.;.;.;.;.;.;.;.;D;.;.;.;D;D
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	.;.;.;D;.;.;.;D;.;.;.;.;D;D;D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.6	.;.;.;.;.;.;.;.;.;H;.;.;.;H;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-6.0	.;.;.;.;D;.;.;.;.;.;.;D;D;D;.
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0050	.;.;.;.;D;.;.;.;.;.;.;D;D;D;.
Sift4G	Pathogenic	0.0	.;.;.;.;.;D;.;.;.;.;.;.;.;D;.
Polyphen		0.99, 0.99	.;D;.;.;.;D;.;D;.;D;.;.;.;D;.
Vest4		0.95, 0.86, 0.95, 0.86, 0.95, 0.96, 0.95
MutPred		0.83		.;.;.;.;.;.;.;.;.;Gain of phosphorylation at G569 (P = 0.0409);.;.;.;Gain of phosphorylation at G569 (P = 0.0409);.;
MVP		0.91
MPC		2.0
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.96
gMVP		0.98

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: rs1555393242; hg19: chr15-25605587;