15-25339124-GTTTTGTTTTGTTTTA-G

Position:

• chr15-25339124-GTTTTGTTTTGTTTTA-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_130839.5(UBE3A):​c.2617_*12delTAAAACAAAACAAAA​(p.Ter873del) variant causes a stop lost, conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. *873*) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: UBE3A NM_130839.5 stop_lost, conservative_inframe_deletion
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.932

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 12 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 15-25339124-GTTTTGTTTTGTTTTA-G is Pathogenic according to our data. Variant chr15-25339124-GTTTTGTTTTGTTTTA-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 987033.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-25339124-GTTTTGTTTTGTTTTA-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UBE3A	NM_130839.5	c.2617_*12delTAAAACAAAACAAAA	p.Ter873del	stop_lost, conservative_inframe_deletion	13/13	ENST00000648336.2	NP_570854.1
UBE3A	NM_130839.5	c.2609_*12delTAAAACAAAACAAAA		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.2617_*12delTAAAACAAAACAAAA	p.Ter873del	stop_lost, conservative_inframe_deletion	13/13		NM_130839.5	ENSP00000497572.2
UBE3A	ENST00000648336	c.2609_*12delTAAAACAAAACAAAA		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: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Oct 23, 2020

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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: rs2074282420; hg19: chr15-25584271;