chr15-25355883-A-G

Variant names:

• chr15-25355883-A-G
• rs79328837
• NM_130839.5:c.2124+9T>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BA1 BP4

This summary comes from the ClinGen Evidence Repository: The allele frequency of the c.2064+9T>C variant in UBE3A is 0.4% 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. Splice prediction analysis, using multiple computational tools does not suggest an impact to splicing (BP4). In summary, the c.2064+9T>C variant in UBE3A is classified as benign based on the ACMG/AMP criteria (BA1, BP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA149405/MONDO:0007113/016

• Frequency:
  • Genomes: 𝑓 0.0044 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (21 hom.)
• Consequence: UBE3A NM_130839.5 intron
• Clinical Significance: Benign reviewed by expert panel U:1 B:11
• Conservation: PhyloP100: 0.286
• 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 -9 ACMG points.

• BP4: 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBE3A	NM_130839.5	MANE Select	c.2124+9T>C		intron	N/A	NP_570854.1
	UBE3A	NM_000462.5		c.2133+9T>C		intron	N/A	NP_000453.2
	UBE3A	NM_001354505.1		c.2124+9T>C		intron	N/A	NP_001341434.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBE3A	ENST00000648336.2	MANE Select	c.2124+9T>C		intron	N/A	ENSP00000497572.2
	UBE3A	ENST00000566215.5	TSL:1	c.2064+9T>C		intron	N/A	ENSP00000457771.1
	SNHG14	ENST00000424333.6	TSL:1	n.5767-62905A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00434 AC: 661 AN: 152170 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0102

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00811

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00513

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.00442 AC: 1108 AN: 250526 AF XY: 0.00443

Gnomad AFR exome AF: 0.000556

Gnomad AMR exome AF: 0.00663

Gnomad ASJ exome AF: 0.00577

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00699

Gnomad NFE exome AF: 0.00544

Gnomad OTH exome AF: 0.00541

GnomAD4 exome AF: 0.00425 AC: 6190 AN: 1457940 Hom.: 21 Cov.: 31 AF XY: 0.00420 AC XY: 3044 AN XY: 725522

African (AFR) AF: 0.00102 AC: 34 AN: 33366

American (AMR) AF: 0.00647 AC: 289 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.00510 AC: 133 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39554

South Asian (SAS) AF: 0.000314 AC: 27 AN: 86120

European-Finnish (FIN) AF: 0.00736 AC: 393 AN: 53384

Middle Eastern (MID) AF: 0.00826 AC: 40 AN: 4840

European-Non Finnish (NFE) AF: 0.00449 AC: 4987 AN: 1109714

Other (OTH) AF: 0.00477 AC: 287 AN: 60188

GnomAD4 genome AF: 0.00437 AC: 665 AN: 152284 Hom.: 2 Cov.: 32 AF XY: 0.00481 AC XY: 358 AN XY: 74462

African (AFR) AF: 0.000794 AC: 33 AN: 41566

American (AMR) AF: 0.0102 AC: 156 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00519 AC: 18 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00811 AC: 86 AN: 10610

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.00515 AC: 350 AN: 68014

Other (OTH) AF: 0.00662 AC: 14 AN: 2114

Alfa AF: 0.00403 Hom.: 2

Bravo AF: 0.00417

EpiCase AF: 0.00627

EpiControl AF: 0.00683

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	1	2	Angelman syndrome (3)
-	-	2	not provided (2)
-	-	1	UBE3A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	6.3
DANN	Benign	0.75
PhyloP100		0.29
PromoterAI		0.0098	Neutral
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: rs79328837; hg19: chr15-25601030;