rs587781238

Variant names:

• chr15-25340114-AATC-A
• rs587781238
• NM_130839.5:c.2466_2468delGAT

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM4_Supporting PP5_Moderate

The ENST00000648336.2(UBE3A):​c.2466_2468delGAT​(p.Met822del) variant causes a disruptive inframe deletion 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: 32)
• Consequence: UBE3A ENST00000648336.2 disruptive_inframe_deletion
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.02
• 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in ENST00000648336.2
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in ENST00000648336.2. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 15-25340114-AATC-A is Pathogenic according to our data. Variant chr15-25340114-AATC-A is described in ClinVar as Pathogenic. ClinVar VariationId is 155991.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000648336.2. 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.2466_2468delGAT	p.Met822del	disruptive_inframe_deletion	Exon 12 of 13	NP_570854.1
	UBE3A	NM_000462.5		c.2475_2477delGAT	p.Met825del	disruptive_inframe_deletion	Exon 13 of 14	NP_000453.2
	UBE3A	NM_001354505.1		c.2466_2468delGAT	p.Met822del	disruptive_inframe_deletion	Exon 12 of 13	NP_001341434.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBE3A	ENST00000648336.2	MANE Select	c.2466_2468delGAT	p.Met822del	disruptive_inframe_deletion	Exon 12 of 13	ENSP00000497572.2
	UBE3A	ENST00000566215.5	TSL:1	c.2406_2408delGAT	p.Met802del	disruptive_inframe_deletion	Exon 14 of 15	ENSP00000457771.1
	SNHG14	ENST00000424333.6	TSL:1	n.5766+61234_5766+61236delATC		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Angelman syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.0
Mutation Taster		=7/93	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs587781238; hg19: chr15-25585261;