rs587781241

Positions:

• chr15-25371797-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2_Supporting PS4_Supporting PM5 PS3_Supporting PP1_Strong PP3

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

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:):

ACMG classification

Verdict is Pathogenic. Variant got 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/exons	MANE	Protein	UniProt
UBE3A	NM_130839.5	c.377C>A	p.Thr126Lys	missense_variant	6/13	ENST00000648336.2	NP_570854.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UBE3A	ENST00000648336.2	c.377C>A	p.Thr126Lys	missense_variant	6/13		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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Angelman syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Baylor Genetics	Feb 14, 2014	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Mar 26, 2021	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;.;.;.
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs587781241; hg19: chr15-25616944; COSMIC: COSV99217511; COSMIC: COSV99217511;