rs1557871

chr15-25336066-T-C

Variant summary

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

The NM_130839.5(UBE3A):c.*3071A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.119 in 152,164 control chromosomes in the GnomAD database, including 1,163 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 (1163 hom., cov: 32)
  • Exomes 𝑓: 0.071 (0 hom.)
• Consequence: UBE3A NM_130839.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.969

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=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.139 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UBE3A	NM_130839.5	c.*3071A>G		3_prime_UTR_variant	13/13	ENST00000648336.2
SNHG14	NR_146177.1	n.18393-55530T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UBE3A	ENST00000648336.2	c.*3071A>G		3_prime_UTR_variant	13/13		NM_130839.5	P1
SNHG14	ENST00000656420.1	n.5456+57182T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.120 AC: 18167 AN: 152002 Hom.: 1164 Cov.: 32

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.147

Gnomad AMR AF: 0.0931

Gnomad ASJ AF: 0.113

Gnomad EAS AF: 0.000964

Gnomad SAS AF: 0.0876

Gnomad FIN AF: 0.0970

Gnomad MID AF: 0.240

Gnomad NFE AF: 0.126

Gnomad OTH AF: 0.125

GnomAD4 exome AF: 0.0714 AC: 3 AN: 42 Hom.: 0 Cov.: 0 AF XY: 0.0357 AC XY: 1 AN XY: 28

Gnomad4 EAS exome AF: 0.00

Gnomad4 NFE exome AF: 0.0750

GnomAD4 genome AF: 0.119 AC: 18173 AN: 152122 Hom.: 1163 Cov.: 32 AF XY: 0.116 AC XY: 8640 AN XY: 74360

Gnomad4 AFR AF: 0.142

Gnomad4 AMR AF: 0.0928

Gnomad4 ASJ AF: 0.113

Gnomad4 EAS AF: 0.000966

Gnomad4 SAS AF: 0.0874

Gnomad4 FIN AF: 0.0970

Gnomad4 NFE AF: 0.126

Gnomad4 OTH AF: 0.124

Alfa AF: 0.117 Hom.: 175

Bravo AF: 0.120

Asia WGS AF: 0.0480 AC: 168 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	1.3
Dann	Benign	0.57

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1557871; hg19: chr15-25581213;