rs1555399937

Positions:

• chr15-25370670-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_130839.5(UBE3A):​c.1504C>T​(p.Arg502*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: UBE3A NM_130839.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 3.86

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-25370670-G-A is Pathogenic according to our data. Variant chr15-25370670-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 446052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UBE3A	NM_130839.5	c.1504C>T	p.Arg502*	stop_gained	6/13	ENST00000648336.2	NP_570854.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UBE3A	ENST00000648336.2	c.1504C>T	p.Arg502*	stop_gained	6/13		NM_130839.5	ENSP00000497572.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Angelman syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000446052, PMID:9585605). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 08, 2020	Based on the classification scheme VCGS_Germline_v0.6.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease for this gene. 0107 - This gene is known to be associated with autosomal dominant disease. 0113 - This gene is known to be imprinted (OMIM). 0202 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein BUT is located in an exon that may undergo alternative splicing (exon 3 of 10). 0301 - Variant is absent from gnomAD. 0401 - Variant is located in a gene associated with a severe early onset DOMINANT condition that is INTOLERANT to loss-of-function variants. 0507 - Identified variant type is not compatible with in silico predictions of pathogenicity. 0701 - Comparable variant in relevant codon/region has very strong previous evidence for pathogenicity. At least 10 variants predicted to cause NMD have been reported as pathogenic in individuals with Angelman syndrome (ClinVar). 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been previously reported in patients with Angelman syndrome (PMIDs:11748306, 10737998). 0905 - No published segregation evidence has been identified for this variant. 1007 - No published functional evidence has been identified for this variant. 1204 - De Novo Variant (Parental status not tested but assumed). -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2020	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in UBE3A are known to be pathogenic (PMID: 25212744). This variant has been observed in several individuals with clinical features of Angelman syndrome (PMID: 9585605, 25212744, Invitae). ClinVar contains an entry for this variant (Variation ID: 446052). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Arg482*) in the UBE3A gene. It is expected to result in an absent or disrupted protein product. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Sep 06, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.96	D
Vest4		0.97, 0.97, 0.97, 0.97
GERP RS		4.5

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: rs1555399937; hg19: chr15-25615817;