rs863225070

Positions:

• chr15-25339187-CTTTAAG-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PP4 PM2_Supporting PS4 PM4_Supporting PS2

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 inframe_deletion
• Clinical Significance: Pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 10.0

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

Verdict is Pathogenic. Variant got 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UBE3A	NM_130839.5	c.2563_2568del	p.Leu855_Lys856del	inframe_deletion	13/13	ENST00000648336.2	NP_570854.1
SNHG14	NR_146177.1	n.18393-52405_18393-52400del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UBE3A	ENST00000648336.2	c.2563_2568del	p.Leu855_Lys856del	inframe_deletion	13/13		NM_130839.5	ENSP00000497572	P1
SNHG14	ENST00000656420.1	n.5456+60307_5456+60312del		intron_variant, non_coding_transcript_variant

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

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:3

Likely pathogenic, no assertion criteria provided	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Mar 06, 2015	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 31, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 24, 2019	Reported using alternate nomenclature c.3090_3095delCTTAAA in two unrelated patients with Angelman syndrome in published literature (Goto et al., 2015); In-frame deletion of two amino acids in a non-repeat region; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 24796722) -

Angelman syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 18, 2021	For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with clinical features of Angelman syndrome (PMID: 24796722). In at least one individual the variant was observed to be de novo. This variant is also known as 3090_3095delCTTAAA (p.853_854delLK). ClinVar contains an entry for this variant (Variation ID: 217365). This variant is not present in population databases (ExAC no frequency). This variant, c.2503_2508del, results in the deletion of 2 amino acid(s) of the UBE3A protein (p.Leu835_Lys836del), but otherwise preserves the integrity of the reading frame. -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	The variant is not observed in the gnomAD v2.1.1 dataset. Inframe deletion located in a nonrepeat region was predicted to change the length of the protein and disrupt normal protein function. The variant has been reported multiple times as an established pathogenic variant (ClinVar ID: VCV000217365 / PMID: 24796722). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Jun 30, 2022	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). -

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: rs863225070; hg19: chr15-25584334;