15-25339114-G-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_130839.5(UBE3A):c.*23C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0085 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: UBE3A NM_130839.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.00

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 15-25339114-G-T is Benign according to our data. Variant chr15-25339114-G-T is described in ClinVar as [Benign]. Clinvar id is 1292518.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome at 2035 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UBE3A	NM_130839.5	c.*23C>A		3_prime_UTR_variant	13/13	ENST00000648336.2
SNHG14	NR_146177.1	n.18393-52482G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UBE3A	ENST00000648336.2	c.*23C>A		3_prime_UTR_variant	13/13		NM_130839.5	P1
SNHG14	ENST00000656420.1	n.5456+60230G>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00 AC: 23 AN: 135732 Hom.: 0 Cov.: 32 FAILED QC

Gnomad AFR AF: 0.0000816

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000218

Gnomad ASJ AF: 0.000320

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000232

Gnomad FIN AF: 0.000932

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000114

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0184 AC: 2035 AN: 110544 Hom.: 0 AF XY: 0.0166 AC XY: 1026 AN XY: 61818

Gnomad AFR exome AF: 0.0195

Gnomad AMR exome AF: 0.0260

Gnomad ASJ exome AF: 0.0165

Gnomad EAS exome AF: 0.0641

Gnomad SAS exome AF: 0.0106

Gnomad FIN exome AF: 0.00331

Gnomad NFE exome AF: 0.0172

Gnomad OTH exome AF: 0.0326

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00851 AC: 10379 AN: 1219996 Hom.: 0 Cov.: 30 AF XY: 0.00938 AC XY: 5568 AN XY: 593630

Gnomad4 AFR exome AF: 0.0115

Gnomad4 AMR exome AF: 0.0298

Gnomad4 ASJ exome AF: 0.0155

Gnomad4 EAS exome AF: 0.0232

Gnomad4 SAS exome AF: 0.0376

Gnomad4 FIN exome AF: 0.00650

Gnomad4 NFE exome AF: 0.00594

Gnomad4 OTH exome AF: 0.0105

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000169 AC: 23 AN: 135826 Hom.: 0 Cov.: 32 AF XY: 0.000197 AC XY: 13 AN XY: 65880

Gnomad4 AFR AF: 0.0000814

Gnomad4 AMR AF: 0.000218

Gnomad4 ASJ AF: 0.000320

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000233

Gnomad4 FIN AF: 0.000932

Gnomad4 NFE AF: 0.000114

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 06, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.41
Dann	Benign	0.35

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: rs955490436; hg19: chr15-25584261;