rs1557874

Positions:

• chr15-25343337-C-A
• chr15-25343337-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_130839.5(UBE3A):​c.2355-3109G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.116 in 152,132 control chromosomes in the GnomAD database, including 1,079 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 0.12 (1079 hom., cov: 32)
• Consequence: UBE3A NM_130839.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.326

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=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.128 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UBE3A	NM_130839.5	c.2355-3109G>T		intron_variant		ENST00000648336.2
SNHG14	NR_146177.1	n.18393-48259C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UBE3A	ENST00000648336.2	c.2355-3109G>T		intron_variant			NM_130839.5	P1
SNHG14	ENST00000656420.1	n.5456+64453C>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.116 AC: 17599 AN: 152014 Hom.: 1080 Cov.: 32

Gnomad AFR AF: 0.131

Gnomad AMI AF: 0.130

Gnomad AMR AF: 0.0915

Gnomad ASJ AF: 0.113

Gnomad EAS AF: 0.000965

Gnomad SAS AF: 0.0876

Gnomad FIN AF: 0.0974

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.125

Gnomad OTH AF: 0.122

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

GnomAD4 genome AF: 0.116 AC: 17603 AN: 152132 Hom.: 1079 Cov.: 32 AF XY: 0.112 AC XY: 8362 AN XY: 74366

Gnomad4 AFR AF: 0.131

Gnomad4 AMR AF: 0.0913

Gnomad4 ASJ AF: 0.113

Gnomad4 EAS AF: 0.000967

Gnomad4 SAS AF: 0.0875

Gnomad4 FIN AF: 0.0974

Gnomad4 NFE AF: 0.125

Gnomad4 OTH AF: 0.121

Alfa AF: 0.106 Hom.: 464

Bravo AF: 0.115

Asia WGS AF: 0.0460 AC: 162 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.0
DANN	Benign	0.74

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: rs1557874; hg19: chr15-25588484;