rs587781232

Variant names:

• chr15-25339130-TTTTGTTTTAC-T
• rs587781232
• NM_130839.5:c.2616_*6delGTAAAACAAA

Variant summary

Our verdict is Pathogenic. The variant received 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 (★★). Synonymous variant affecting the same amino acid position (i.e. L872L) has been classified as Likely benign.

• 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
• Publications: 1 publications found

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:37462): (small nucleolar RNA host gene 14) This gene is located within the Prader-Willi critical region and produces a long, spliced paternally-imprinted RNA that initiates within a common upstream promoter region shared by the SNRPN (small nuclear ribonucleoprotein polypeptide N) and SNURF genes. This transcript serves as a host RNA for the small nucleolar RNA, C/D box 115 and 116 clusters. This RNA extends in antisense into the region of the ubiquitin protein ligase E3A gene (UBE3A), and is thought to regulate imprinted expression of UBE3A in the brain. This transcript undergoes extensive alternative splicing, and may initiate and terminate at multiple locations within this genomic region. The full-length structure of all splice forms is not determined. [provided by RefSeq, Mar 2017]

ACMG classification

Our verdict: Pathogenic. The variant received 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 VariationId is 155985.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_130839.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBE3A	NM_130839.5	MANE Select	c.2616_*6delGTAAAACAAA	p.Leu872fs	frameshift stop_lost	Exon 13 of 13	NP_570854.1
	UBE3A	NM_130839.5	MANE Select	c.2616_*6delGTAAAACAAA		3_prime_UTR	Exon 13 of 13	NP_570854.1
	UBE3A	NM_000462.5		c.2625_*6delGTAAAACAAA	p.Leu875fs	frameshift stop_lost	Exon 14 of 14	NP_000453.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBE3A	ENST00000648336.2	MANE Select	c.2616_*6delGTAAAACAAA	p.Leu872fs	frameshift stop_lost	Exon 13 of 13	ENSP00000497572.2
	UBE3A	ENST00000566215.5	TSL:1	c.2556_*6delGTAAAACAAA	p.Leu852fs	frameshift stop_lost	Exon 15 of 15	ENSP00000457771.1
	UBE3A	ENST00000648336.2	MANE Select	c.2616_*6delGTAAAACAAA		3_prime_UTR	Exon 13 of 13	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

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Angelman syndrome (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.3
Mutation Taster		=5/195	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs587781232; hg19: chr15-25584277;