rs587781232

Positions:

• chr15-25339130-TTTTGTTTTAC-T

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.2616_*6delGTAAAACAAA​(p.Leu872fs) variant causes a frameshift, stop lost change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: UBE3A NM_130839.5 frameshift, stop_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.32

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: Stoplost variant. No alternative stopcodon identified downstream, so we assume a Nonstop Mediated Decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-25339130-TTTTGTTTTAC-T is Pathogenic according to our data. Variant chr15-25339130-TTTTGTTTTAC-T is described in ClinVar as [Pathogenic]. Clinvar id is 155985.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.2616_*6delGTAAAACAAA	p.Leu872fs	frameshift_variant, stop_lost	13/13	ENST00000648336.2	NP_570854.1
UBE3A	NM_130839.5	c.2617_*6delGTAAAACAAA		3_prime_UTR_variant	13/13	ENST00000648336.2	NP_570854.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UBE3A	ENST00000648336.2	c.2616_*6delGTAAAACAAA	p.Leu872fs	frameshift_variant, stop_lost	13/13		NM_130839.5	ENSP00000497572.2
UBE3A	ENST00000648336	c.2617_*6delGTAAAACAAA		3_prime_UTR_variant	13/13		NM_130839.5	ENSP00000497572.2

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Angelman syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Baylor Genetics	Feb 14, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 22, 2016	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 25, 2024

Identified in a patient with mild developmental delay, moderate speech delay, and no seizures in published literature (PMID: 22566713); Stop codon loss and change to a Gln codon, leading to protein extension and the addition of 16 amino acids at the C-terminus in a gene for which protein extension is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22566713) -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587781232; hg19: chr15-25584277;