15-25350665-C-T

Position:

• chr15-25350665-C-T

Variant summary

Our verdict is Benign. Variant got -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

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

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
UBE3A	NM_130839.5	c.2354+3688G>A		intron_variant		ENST00000648336.2	NP_570854.1
SNHG14	NR_146177.1	n.18393-40931C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UBE3A	ENST00000648336.2	c.2354+3688G>A		intron_variant			NM_130839.5	ENSP00000497572	P1
SNHG14	ENST00000656420.1	n.5457-68123C>T		intron_variant, non_coding_transcript_variant

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

Gnomad4 AFR AF: 0.826

Gnomad4 AMR AF: 0.337

Gnomad4 ASJ AF: 0.307

Gnomad4 EAS AF: 0.426

Gnomad4 SAS AF: 0.328

Gnomad4 FIN AF: 0.336

Gnomad4 NFE AF: 0.304

Gnomad4 OTH AF: 0.423

Alfa AF: 0.322 Hom.: 11386

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs4445877; hg19: chr15-25595812;