15-25339090-CT-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_130839.5(UBE3A):c.*46del variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000114 in 1,461,526 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (2 hom.)
• Consequence: UBE3A NM_130839.5 3_prime_UTR
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: -0.00200

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 Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAd at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UBE3A	NM_130839.5	c.*46del		3_prime_UTR_variant	13/13	ENST00000648336.2
SNHG14	NR_146177.1	n.18393-52497del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UBE3A	ENST00000648336.2	c.*46del		3_prime_UTR_variant	13/13		NM_130839.5	P1
SNHG14	ENST00000656420.1	n.5456+60215del		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000133 AC: 20 AN: 150314 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000244

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000133

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.000210

Gnomad FIN AF: 0.0000974

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000742

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000111 AC: 146 AN: 1311102 Hom.: 2 Cov.: 30 AF XY: 0.000112 AC XY: 72 AN XY: 644092

Gnomad4 AFR exome AF: 0.000928

Gnomad4 AMR exome AF: 0.0000482

Gnomad4 ASJ exome AF: 0.0000464

Gnomad4 EAS exome AF: 0.000147

Gnomad4 SAS exome AF: 0.000105

Gnomad4 FIN exome AF: 0.000460

Gnomad4 NFE exome AF: 0.0000749

Gnomad4 OTH exome AF: 0.000148

GnomAD4 genome AF: 0.000133 AC: 20 AN: 150424 Hom.: 0 Cov.: 32 AF XY: 0.000136 AC XY: 10 AN XY: 73464

Gnomad4 AFR AF: 0.000244

Gnomad4 AMR AF: 0.000133

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000195

Gnomad4 SAS AF: 0.000211

Gnomad4 FIN AF: 0.0000974

Gnomad4 NFE AF: 0.0000742

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000869

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Angelman syndrome Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Baylor Genetics

Feb 14, 2014

possible diagnosis of Angelman syndrome -

Computational scores

Source: dbNSFP v4.3

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: rs368425414; hg19: chr15-25584237;