chr15-25371556-T-A

Variant names:

• chr15-25371556-T-A
• rs143484751
• NM_130839.5:c.618A>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP7 BA1 BP4

This summary comes from the ClinGen Evidence Repository: The allele frequency of the c.558A>T p.(Ala186=) variant in UBE3A (NM_130838.2) is 0.047% 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.558A>T p.(Ala186=) variant in UBE3A is classified as Benign based on the ACMG/AMP criteria (BA1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA291604/MONDO:0007113/016

• Frequency:
  • Genomes: 𝑓 0.00037 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: UBE3A NM_130839.5 synonymous
• Clinical Significance: Benign reviewed by expert panel U:1 B:6
• Conservation: PhyloP100: -0.892
• Publications: 4 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 -10 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: For more information check the summary or visit ClinGen Evidence Repository.
• 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.618A>T	p.Ala206Ala	synonymous	Exon 6 of 13	NP_570854.1
	UBE3A	NM_000462.5		c.627A>T	p.Ala209Ala	synonymous	Exon 7 of 14	NP_000453.2
	UBE3A	NM_001354505.1		c.618A>T	p.Ala206Ala	synonymous	Exon 6 of 13	NP_001341434.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBE3A	ENST00000648336.2	MANE Select	c.618A>T	p.Ala206Ala	synonymous	Exon 6 of 13	ENSP00000497572.2
	UBE3A	ENST00000566215.5	TSL:1	c.558A>T	p.Ala186Ala	synonymous	Exon 8 of 15	ENSP00000457771.1
	SNHG14	ENST00000424333.6	TSL:1	n.5767-47232T>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000368 AC: 56 AN: 152232 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000573

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000231 AC: 58 AN: 251428 AF XY: 0.000235

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 FIN exome AF: 0.00120

Gnomad NFE exome AF: 0.000255

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000194 AC: 284 AN: 1461866 Hom.: 0 Cov.: 32 AF XY: 0.000212 AC XY: 154 AN XY: 727234

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00118 AC: 63 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000188 AC: 209 AN: 1112000

Other (OTH) AF: 0.000199 AC: 12 AN: 60394

GnomAD4 genome AF: 0.000368 AC: 56 AN: 152350 Hom.: 1 Cov.: 32 AF XY: 0.000376 AC XY: 28 AN XY: 74508

African (AFR) AF: 0.00 AC: 0 AN: 41594

American (AMR) AF: 0.00 AC: 0 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00132 AC: 14 AN: 10622

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

European-Non Finnish (NFE) AF: 0.000573 AC: 39 AN: 68032

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.000711 Hom.: 1

Bravo AF: 0.0000907

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	1.1
DANN	Benign	0.59
PhyloP100		-0.89
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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: rs143484751; hg19: chr15-25616703; COSMIC: COSV108021546;