rs863225071

Positions:

• chr15-25371167-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PS2 PP4

This summary comes from the ClinGen Evidence Repository: The c.947T>C p.(Met316Thr) variant in UBE3A (NM_130838.2) is present in gnomAD v2.1.1 at a frequency of 0.003% in the Latino/Admixed sub population (no criteria met). The p.(Met316Thr) variant in UBE3A has been reported as a de novo occurrence (biological parentage confirmed) in an individual with Angelman syndrome (PMID 27864847) (PS2, PP4), however the gnomAD frequency of this variant means that the PS4 criterion cannot be applied. Computational prediction analysis tools are inconclusive for this variant. In summary, the c.947T>C p.(Met316Thr) variant in UBE3A is classified as a variant of uncertain significance based on the ACMG/AMP criteria (PS2, PP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA279176/MONDO:0007113/016

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: UBE3A NM_130839.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:3
• Conservation: PhyloP100: 9.32

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 5 ACMG points.

• PS2: 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.1007T>C	p.Met336Thr	missense_variant	6/13	ENST00000648336.2	NP_570854.1
SNHG14	NR_146177.1	n.18393-20429A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UBE3A	ENST00000648336.2	c.1007T>C	p.Met336Thr	missense_variant	6/13		NM_130839.5	ENSP00000497572	P1
SNHG14	ENST00000656420.1	n.5457-47621A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251340 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135842

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461846 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727224

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

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: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:3

Revision: reviewed by expert panel

Submissions by phenotype

Angelman syndrome Pathogenic:1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 15, 2022	Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. ClinVar contains an entry for this variant (Variation ID: 217366). This variant has not been reported in the literature in individuals affected with UBE3A-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 316 of the UBE3A protein (p.Met316Thr). -
Uncertain significance, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Jun 30, 2022	The c.947T>C p.(Met316Thr) variant in UBE3A (NM_130838.2) is present in gnomAD v2.1.1 at a frequency of 0.003% in the Latino/Admixed sub population (no criteria met). The p.(Met316Thr) variant in UBE3A has been reported as a de novo occurrence (biological parentage confirmed) in an individual with Angelman syndrome (PMID 27864847) (PS2, PP4), however the gnomAD frequency of this variant means that the PS4 criterion cannot be applied. Computational prediction analysis tools are inconclusive for this variant. In summary, the c.947T>C p.(Met316Thr) variant in UBE3A is classified as a variant of uncertain significance based on the ACMG/AMP criteria (PS2, PP4). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Neurogenetics Laboratory - MEYER, AOU Meyer	Nov 16, 2016	Correct nomenclature and coordinates: Chr15(GRCh37):g.25616383A>G NM_130839.5(UBE3A):c.1007T>C p.(Leu293Pro) The variant is reported in Parrini et al 2017, PMID 27864847 (Pt 628N, Table S12) -

not specified Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Mar 06, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Uncertain	0.021	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	.;.;.;.;.;.;.;.;.;T;.;.;.;T;T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	.;.;.;D;.;.;.;D;.;.;.;.;D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.52	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	.;.;.;.;.;.;.;.;.;L;.;.;.;L;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.0	.;.;.;.;D;.;.;.;.;.;.;D;D;D;.
REVEL	Benign	0.25
Sift	Uncertain	0.0070	.;.;.;.;D;.;.;.;.;.;.;D;D;D;.
Sift4G	Uncertain	0.010	.;.;.;.;.;D;.;.;.;.;.;.;.;D;.
Polyphen		0.23, 0.049	.;B;.;.;.;B;.;B;.;B;.;.;.;B;.
Vest4		0.70, 0.68, 0.71, 0.68, 0.71, 0.72, 0.70
MutPred		0.59		.;.;.;.;.;.;.;.;.;Loss of stability (P = 0.0471);.;.;.;Loss of stability (P = 0.0471);.;
MVP		0.27
MPC		1.1
ClinPred		0.56	D
GERP RS		5.7
Varity_R		0.54
gMVP		0.77

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: rs863225071; hg19: chr15-25616314;