rs8179187

Variant names:

• chr15-25407179-T-G
• rs8179187
• ENST00000566215.5:c.-153A>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_001354507.2(UBE3A):​c.-153A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0769 in 1,341,490 control chromosomes in the GnomAD database, including 5,322 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 0.073 (698 hom., cov: 32)
  • Exomes 𝑓: 0.077 (4624 hom.)
• Consequence: UBE3A NM_001354507.2 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.555

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.298 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UBE3A	NM_130839.5	c.21-1677A>C		intron_variant	Intron 3 of 12	ENST00000648336.2	NP_570854.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UBE3A	ENST00000648336.2	c.21-1677A>C		intron_variant	Intron 3 of 12		NM_130839.5	ENSP00000497572.2

Frequencies

GnomAD3 genomes AF: 0.0732 AC: 11130 AN: 152106 Hom.: 697 Cov.: 32

Gnomad AFR AF: 0.0199

Gnomad AMI AF: 0.116

Gnomad AMR AF: 0.131

Gnomad ASJ AF: 0.0804

Gnomad EAS AF: 0.311

Gnomad SAS AF: 0.110

Gnomad FIN AF: 0.0735

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0711

Gnomad OTH AF: 0.0655

GnomAD2 exomes AF: 0.109 AC: 23403 AN: 215128 AF XY: 0.104

Gnomad AFR exome AF: 0.0200

Gnomad AMR exome AF: 0.195

Gnomad ASJ exome AF: 0.0695

Gnomad EAS exome AF: 0.308

Gnomad FIN exome AF: 0.0797

Gnomad NFE exome AF: 0.0692

Gnomad OTH exome AF: 0.0921

GnomAD4 exome AF: 0.0774 AC: 92013 AN: 1189266 Hom.: 4624 Cov.: 30 AF XY: 0.0777 AC XY: 45815 AN XY: 589272

Gnomad4 AFR exome AF: 0.0181 AC: 463 AN: 25622

Gnomad4 AMR exome AF: 0.192 AC: 6878 AN: 35804

Gnomad4 ASJ exome AF: 0.0689 AC: 1140 AN: 16554

Gnomad4 EAS exome AF: 0.310 AC: 4932 AN: 15918

Gnomad4 SAS exome AF: 0.100 AC: 8188 AN: 81564

Gnomad4 FIN exome AF: 0.0815 AC: 1383 AN: 16966

Gnomad4 NFE exome AF: 0.0687 AC: 65226 AN: 948946

Gnomad4 Remaining exome AF: 0.0852 AC: 3700 AN: 43442

GnomAD4 genome AF: 0.0731 AC: 11134 AN: 152224 Hom.: 698 Cov.: 32 AF XY: 0.0776 AC XY: 5771 AN XY: 74404

Gnomad4 AFR AF: 0.0200 AC: 0.0199528 AN: 0.0199528

Gnomad4 AMR AF: 0.132 AC: 0.131995 AN: 0.131995

Gnomad4 ASJ AF: 0.0804 AC: 0.0803571 AN: 0.0803571

Gnomad4 EAS AF: 0.311 AC: 0.311094 AN: 0.311094

Gnomad4 SAS AF: 0.110 AC: 0.110328 AN: 0.110328

Gnomad4 FIN AF: 0.0735 AC: 0.0735322 AN: 0.0735322

Gnomad4 NFE AF: 0.0711 AC: 0.0711303 AN: 0.0711303

Gnomad4 OTH AF: 0.0639 AC: 0.06386 AN: 0.06386

Alfa AF: 0.0707 Hom.: 852

Bravo AF: 0.0759

Asia WGS AF: 0.187 AC: 652 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	15
DANN	Benign	0.93
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

Publications

LitVar

Other links and lift over

dbSNP: rs8179187; hg19: chr15-25652326; COSMIC: COSV51665364; COSMIC: COSV51665364;