rs587781241

Variant names:

• chr15-25371797-G-T
• rs587781241
• NM_130839.5:c.377C>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PS3_Supporting PP3 PM2_Supporting PS4_Supporting PM5 PP1_Strong

This summary comes from the ClinGen Evidence Repository: The variant has been reported to segregate in at least five informative meioses (PMID 25212744, internal database) (PP1_Strong). A pathogenic missense variant (p.Thr106Pro) has been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 15054837) (PM5). Protein expression analysis in transfected cell lines has shown that this variant reduces protein function (PMID 26255772) PS3_Supporting). The p.Thr106Lys variant has been observed in at least 1 other individual with Angelman syndrome (PMID 25212744) (PS4_Supporting). The p.Thr106Lys variant in UBE3A is absent from gnomAD (PM2_Supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Thr106Lys variant in UBE3A is classified as pathogenic for Angelman syndrome based on the ACMG/AMP criteria (PP1_strong, PM5, PS3_supporting, PS4_supporting, PM2_supporting, PP3). LINK:https://erepo.genome.network/evrepo/ui/classification/CA333390/MONDO:0007113/016

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: UBE3A NM_130839.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 10.0
• Publications: 9 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 10 ACMG points.

• PS3: 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.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UBE3A	NM_130839.5	c.377C>A	p.Thr126Lys	missense_variant	Exon 6 of 13	ENST00000648336.2	NP_570854.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UBE3A	ENST00000648336.2	c.377C>A	p.Thr126Lys	missense_variant	Exon 6 of 13		NM_130839.5	ENSP00000497572.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1457226 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 725124

African (AFR) AF: 0.00 AC: 0 AN: 33386

American (AMR) AF: 0.00 AC: 0 AN: 44604

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 86128

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49894

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111356

Other (OTH) AF: 0.00 AC: 0 AN: 60320

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Angelman syndrome Pathogenic:3

Feb 14, 2014

Baylor Genetics

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 26, 2021

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The variant has been reported to segregate in at least five informative meioses (PMID 25212744, internal database) (PP1_Strong). A pathogenic missense variant (p.Thr106Pro) has been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 15054837) (PM5). Protein expression analysis in transfected cell lines has shown that this variant reduces protein function (PMID 26255772) PS3_Supporting). The p.Thr106Lys variant has been observed in at least 1 other individual with Angelman syndrome (PMID 25212744) (PS4_Supporting). The p.Thr106Lys variant in UBE3A is absent from gnomAD (PM2_Supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Thr106Lys variant in UBE3A is classified as pathogenic for Angelman syndrome based on the ACMG/AMP criteria (PP1_strong, PM5, PS3_supporting, PS4_supporting, PM2_supporting, PP3). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.28	.;.;.;.;.;.;.;.;.;T;.;.;.;T;T;.;T
Eigen	Uncertain	0.57
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	.;.;.;D;.;.;.;D;.;.;.;.;D;D;D;D;D
M_CAP	Uncertain	0.091	D
MetaRNN	Pathogenic	0.76	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	.;.;.;.;.;.;.;.;.;M;.;.;.;M;.;.;.
PhyloP100		10
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.6	.;.;.;.;D;.;.;.;.;.;.;D;D;D;.;.;.
REVEL	Pathogenic	0.76
Sift	Benign	0.049	.;.;.;.;D;.;.;.;.;.;.;D;D;D;.;.;.
Sift4G	Benign	0.68	.;.;.;.;.;T;.;.;.;.;.;.;.;T;.;D;.
Polyphen		0.73, 0.65	.;P;.;.;.;P;.;P;.;P;.;.;.;P;.;.;.
Vest4		0.92, 0.87, 0.81, 0.79, 0.81, 0.83, 0.89, 0.84
MutPred		0.42		.;.;.;.;.;.;.;.;.;Gain of ubiquitination at T129 (P = 0.0219);.;.;.;Gain of ubiquitination at T129 (P = 0.0219);.;.;.;
MVP		0.50
MPC		1.8
ClinPred		0.94	D
GERP RS		5.8
Varity_R		0.47
gMVP		0.71
Mutation Taster		=1/99	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: rs587781241; hg19: chr15-25616944; COSMIC: COSV99217511; COSMIC: COSV99217511;