rs587784521

Positions:

• chr15-25356785-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2_Supporting PS4_Supporting PM6

This summary comes from the ClinGen Evidence Repository: The c.1805A>G p.(Asn602Ser) variant in UBE3A (NM_130838.2) is absent from gnomAD (PM2_supporting). The p.(Asn602Ser) variant has been observed in at least 2 individuals with a neurodevelopmental phenotype consistent with UBE3A-related disease (ClinVar SCV000195356.1, SCV000741231.2) (PS4_supporting), where it has been reported as a de novo occurrence (biological parentage unconfirmed) in 1 of these individuals (ClinVar SCV000741231.2) (PM6). Computational prediction analysis tools are inconclusive for this variant. In summary, the c.1805A>G p.(Asn602Ser) variant in UBE3A is classified as a Variant of Uncertain Significance based on the ACMG/AMP criteria (PM6_moderate, PS4_supporting, PM2_supporting). LINK:https://erepo.genome.network/evrepo/ui/classification/CA333543/MONDO:0007113/016

• Frequency: Genomes: not found (cov: 32)
• Consequence: UBE3A NM_130839.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:2
• Conservation: PhyloP100: 8.02

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 Uncertain_significance. Variant got 4 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: 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.1865A>G	p.Asn622Ser	missense_variant	8/13	ENST00000648336.2	NP_570854.1
SNHG14	NR_146177.1	n.18393-34811T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UBE3A	ENST00000648336.2	c.1865A>G	p.Asn622Ser	missense_variant	8/13		NM_130839.5	ENSP00000497572	P1
SNHG14	ENST00000656420.1	n.5457-62003T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Angelman syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Uncertain significance, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Jun 30, 2022	The c.1805A>G p.(Asn602Ser) variant in UBE3A (NM_130838.2) is absent from gnomAD (PM2_supporting). The p.(Asn602Ser) variant has been observed in at least 2 individuals with a neurodevelopmental phenotype consistent with UBE3A-related disease (ClinVar SCV000195356.1, SCV000741231.2) (PS4_supporting), where it has been reported as a de novo occurrence (biological parentage unconfirmed) in 1 of these individuals (ClinVar SCV000741231.2) (PM6). Computational prediction analysis tools are inconclusive for this variant. In summary, the c.1805A>G p.(Asn602Ser) variant in UBE3A is classified as a Variant of Uncertain Significance based on the ACMG/AMP criteria (PM6_moderate, PS4_supporting, PM2_supporting). -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 12, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	.;.;.;.;.;.;.;.;.;T;.;.;.;T;T
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	.;.;.;D;.;.;.;D;.;.;.;.;D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.032	D
MutationAssessor	Pathogenic	3.1	.;.;.;.;.;.;.;.;.;M;.;.;.;M;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-4.7	.;.;.;.;D;.;.;.;.;.;.;D;D;D;.
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0040	.;.;.;.;D;.;.;.;.;.;.;D;D;D;.
Sift4G	Pathogenic	0.0	.;.;.;.;.;D;.;.;.;.;.;.;.;D;.
Polyphen		1.0	.;D;.;.;.;D;.;D;.;D;.;.;.;D;.
Vest4		0.90, 0.88, 0.93, 0.88, 0.93, 0.92, 0.93
MutPred		0.78		.;.;.;.;.;.;.;.;.;Gain of helix (P = 0.1736);.;.;.;Gain of helix (P = 0.1736);.;
MVP		0.77
MPC		1.8
ClinPred		0.99	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.85
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs587784521; hg19: chr15-25601932;