rs139082033

Variant names:

• chr15-25356883-G-A
• rs139082033
• NM_130839.5:c.1767C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The allele frequency of the c.1707C>T p.(Tyr569=) variant in UBE3A (NM_130838.2) is 0.15% in the European (non-Finnish) sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). In summary, the c.1707C>T p.(Tyr569=) variant in UBE3A is classified as Benign based on the ACMG/AMP criteria (BA1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA205044/MONDO:0007113/016

• Frequency:
  • Genomes: 𝑓 0.00092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (6 hom.)
• Consequence: UBE3A NM_130839.5 synonymous
• Clinical Significance: Benign reviewed by expert panel U:1 B:11
• Conservation: PhyloP100: 1.69
• Publications: 1 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: Benign. The variant received -8 ACMG points.

• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_130839.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBE3A	NM_130839.5	MANE Select	c.1767C>T	p.Tyr589Tyr	synonymous	Exon 8 of 13	NP_570854.1	Q05086-3
	UBE3A	NM_000462.5		c.1776C>T	p.Tyr592Tyr	synonymous	Exon 9 of 14	NP_000453.2
	UBE3A	NM_001354505.1		c.1767C>T	p.Tyr589Tyr	synonymous	Exon 8 of 13	NP_001341434.1	Q05086-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBE3A	ENST00000648336.2	MANE Select	c.1767C>T	p.Tyr589Tyr	synonymous	Exon 8 of 13	ENSP00000497572.2	Q05086-3
	UBE3A	ENST00000566215.5	TSL:1	c.1707C>T	p.Tyr569Tyr	synonymous	Exon 10 of 15	ENSP00000457771.1	Q05086-2
	SNHG14	ENST00000424333.6	TSL:1	n.5767-61905G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000927 AC: 141 AN: 152070 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000781 AC: 196 AN: 251006 AF XY: 0.000825

Gnomad AFR exome AF: 0.000434

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00154

Gnomad OTH exome AF: 0.000655

GnomAD4 exome AF: 0.00165 AC: 2404 AN: 1460800 Hom.: 6 Cov.: 30 AF XY: 0.00158 AC XY: 1148 AN XY: 726742

African (AFR) AF: 0.000269 AC: 9 AN: 33452

American (AMR) AF: 0.000335 AC: 15 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39582

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86190

European-Finnish (FIN) AF: 0.0000937 AC: 5 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00208 AC: 2308 AN: 1111260

Other (OTH) AF: 0.00104 AC: 63 AN: 60344

GnomAD4 genome AF: 0.000920 AC: 140 AN: 152188 Hom.: 0 Cov.: 32 AF XY: 0.000766 AC XY: 57 AN XY: 74414

African (AFR) AF: 0.000217 AC: 9 AN: 41524

American (AMR) AF: 0.000262 AC: 4 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00187 AC: 127 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.00151 Hom.: 0

Bravo AF: 0.000948

EpiCase AF: 0.00142

EpiControl AF: 0.00119

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	1	2	Angelman syndrome (3)
-	-	3	not provided (3)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	7.3
DANN	Benign	0.52
PhyloP100		1.7
PromoterAI		-0.0016	Neutral
Mutation Taster		=98/2	polymorphism

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: rs139082033; hg19: chr15-25602030; COSMIC: COSV104573443; COSMIC: COSV104573443;