rs863225070

Variant names:

• chr15-25339187-CTTTAAG-C
• rs863225070
• NM_130839.5:c.2563_2568delCTTAAA

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PS2 PP4 PM2_Supporting PS4 PM4_Supporting

This summary comes from the ClinGen Evidence Repository: The c.2503_2508del p.(Leu835_Lys836del) variant in UBE3A (NM_130838.2) is absent from gnomAD (PM2_supporting). The p.(Leu835_Lys836del) variant has been observed in at least 5 individuals with a diagnosis of Angelman syndrome or a neurodevelopmental phenotype consistent with UBE3A-related disease (PMID 24796722; ClinVar SCV000829845.4, SCV000491076.2, SCV000332262.4) (PS4, PP4), where it has been reported as a de novo occurrence (biological parentage both confirmed and unconfirmed) in at least 3 of these individuals (ClinVar SCV000491076.2, SCV000829845.4, SCV000332262.4) (PS2_Very strong). The p.(Leu835_Lys836del) variant causes a change in the length of 2 amino acids in the protein due to an in-frame deletion or insertion in a non-repeat region of UBE3A (PM4_supporting). In summary, the c.2503_2508del p.(Leu835_Lys836del) variant in UBE3A is classified as Pathogenic for Angelman syndrome based on the ACMG/AMP criteria (PS2_very strong, PS4_strong, PP4, PM2_supporting, PM4_supporting). LINK:https://erepo.genome.network/evrepo/ui/classification/CA279164/MONDO:0007113/016

• Frequency: Genomes: not found (cov: 32)
• Consequence: UBE3A NM_130839.5 conservative_inframe_deletion
• Clinical Significance: Pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 10.0
• Publications: 0 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 11 ACMG points.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM4: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBE3A	NM_130839.5	MANE Select	c.2563_2568delCTTAAA	p.Leu855_Lys856del	conservative_inframe_deletion	Exon 13 of 13	NP_570854.1
	UBE3A	NM_000462.5		c.2572_2577delCTTAAA	p.Leu858_Lys859del	conservative_inframe_deletion	Exon 14 of 14	NP_000453.2
	UBE3A	NM_001354505.1		c.2563_2568delCTTAAA	p.Leu855_Lys856del	conservative_inframe_deletion	Exon 13 of 13	NP_001341434.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBE3A	ENST00000648336.2	MANE Select	c.2563_2568delCTTAAA	p.Leu855_Lys856del	conservative_inframe_deletion	Exon 13 of 13	ENSP00000497572.2
	UBE3A	ENST00000566215.5	TSL:1	c.2503_2508delCTTAAA	p.Leu835_Lys836del	conservative_inframe_deletion	Exon 15 of 15	ENSP00000457771.1
	SNHG14	ENST00000424333.6	TSL:1	n.5766+60307_5766+60312delAAGTTT		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: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	Angelman syndrome (3)
3	-	-	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		10
Mutation Taster		=2/198	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs863225070; hg19: chr15-25584334;