rs61734190

Variant names:

• chr15-25371801-A-G
• rs61734190
• NM_130839.5:c.373T>C

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.313T>C p.(Leu105=) variant in UBE3A (NM_130838.2) is 7.5% in African/African-American 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.313T>C p.(Leu105=) variant in UBE3A is classified as Benign based on the ACMG/AMP criteria (BA1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA149410/MONDO:0007113/016

• Frequency:
  • Genomes: 𝑓 0.021 (120 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (100 hom.)
• Consequence: UBE3A NM_130839.5 synonymous
• Clinical Significance: Benign reviewed by expert panel U:1 B:7
• Conservation: PhyloP100: 3.35
• Publications: 3 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBE3A	NM_130839.5	MANE Select	c.373T>C	p.Leu125Leu	synonymous	Exon 6 of 13	NP_570854.1
	UBE3A	NM_000462.5		c.382T>C	p.Leu128Leu	synonymous	Exon 7 of 14	NP_000453.2
	UBE3A	NM_001354505.1		c.373T>C	p.Leu125Leu	synonymous	Exon 6 of 13	NP_001341434.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBE3A	ENST00000648336.2	MANE Select	c.373T>C	p.Leu125Leu	synonymous	Exon 6 of 13	ENSP00000497572.2
	UBE3A	ENST00000566215.5	TSL:1	c.313T>C	p.Leu105Leu	synonymous	Exon 8 of 15	ENSP00000457771.1
	SNHG14	ENST00000424333.6	TSL:1	n.5767-46987A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0213 AC: 3247 AN: 152146 Hom.: 120 Cov.: 32

Gnomad AFR AF: 0.0737

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00963

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.0167

GnomAD2 exomes AF: 0.00561 AC: 1380 AN: 245968 AF XY: 0.00423

Gnomad AFR exome AF: 0.0762

Gnomad AMR exome AF: 0.00457

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000546

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000178

Gnomad OTH exome AF: 0.00433

GnomAD4 exome AF: 0.00206 AC: 2999 AN: 1456882 Hom.: 100 Cov.: 32 AF XY: 0.00174 AC XY: 1265 AN XY: 724966

African (AFR) AF: 0.0700 AC: 2334 AN: 33348

American (AMR) AF: 0.00536 AC: 239 AN: 44566

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26094

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

South Asian (SAS) AF: 0.0000581 AC: 5 AN: 86110

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49640

Middle Eastern (MID) AF: 0.00278 AC: 16 AN: 5762

European-Non Finnish (NFE) AF: 0.0000990 AC: 110 AN: 1111392

Other (OTH) AF: 0.00489 AC: 295 AN: 60302

GnomAD4 genome AF: 0.0214 AC: 3251 AN: 152264 Hom.: 120 Cov.: 32 AF XY: 0.0205 AC XY: 1524 AN XY: 74442

African (AFR) AF: 0.0736 AC: 3055 AN: 41532

American (AMR) AF: 0.00962 AC: 147 AN: 15286

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68030

Other (OTH) AF: 0.0165 AC: 35 AN: 2116

Alfa AF: 0.0113 Hom.: 26

Bravo AF: 0.0235

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:7

Revision: reviewed by expert panel

Submissions by phenotype

Angelman syndrome Uncertain:1 Benign:2

Feb 14, 2014

Baylor Genetics

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

possible diagnosis of Angelman syndrome

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 30, 2022

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The allele frequency of the c.313T>C p.(Leu105=) variant in UBE3A (NM_130838.2) is 7.5% in African/African-American 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.313T>C p.(Leu105=) variant in UBE3A is classified as Benign based on the ACMG/AMP criteria (BA1).

not specified Benign:3

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 13, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 20, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Inborn genetic diseases Benign:1

Mar 16, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	7.0
DANN	Benign	0.74
PhyloP100		3.4
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs61734190; hg19: chr15-25616948;