15-25350665-C-T

Variant names:

• chr15-25350665-C-T
• rs4445877
• NM_130839.5:c.2354+3688G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_130839.5(UBE3A):​c.2354+3688G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.459 in 151,962 control chromosomes in the GnomAD database, including 20,003 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.46 (20003 hom., cov: 32)
• Consequence: UBE3A NM_130839.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.06
• Publications: 7 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.819 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UBE3A	NM_130839.5	c.2354+3688G>A		intron_variant	Intron 11 of 12	ENST00000648336.2	NP_570854.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UBE3A	ENST00000648336.2	c.2354+3688G>A		intron_variant	Intron 11 of 12		NM_130839.5	ENSP00000497572.2

Frequencies

GnomAD3 genomes AF: 0.458 AC: 69570 AN: 151844 Hom.: 19938 Cov.: 32

Gnomad AFR AF: 0.826

Gnomad AMI AF: 0.285

Gnomad AMR AF: 0.337

Gnomad ASJ AF: 0.307

Gnomad EAS AF: 0.426

Gnomad SAS AF: 0.327

Gnomad FIN AF: 0.336

Gnomad MID AF: 0.418

Gnomad NFE AF: 0.304

Gnomad OTH AF: 0.419

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.459 AC: 69702 AN: 151962 Hom.: 20003 Cov.: 32 AF XY: 0.454 AC XY: 33743 AN XY: 74282

African (AFR) AF: 0.826 AC: 34276 AN: 41490

American (AMR) AF: 0.337 AC: 5138 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.307 AC: 1063 AN: 3466

East Asian (EAS) AF: 0.426 AC: 2189 AN: 5138

South Asian (SAS) AF: 0.328 AC: 1582 AN: 4824

European-Finnish (FIN) AF: 0.336 AC: 3545 AN: 10548

Middle Eastern (MID) AF: 0.429 AC: 126 AN: 294

European-Non Finnish (NFE) AF: 0.304 AC: 20634 AN: 67924

Other (OTH) AF: 0.423 AC: 889 AN: 2104

Alfa AF: 0.337 Hom.: 16366

Bravo AF: 0.473

Asia WGS AF: 0.406 AC: 1407 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	1.1
DANN	Benign	0.66
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs4445877; hg19: chr15-25595812;