15-25339090-CTTTTTTT-CTTTTTTTT

Variant names:

• chr15-25339090-C-CT
• rs368425414
• NM_130839.5:c.*46dupA

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_130839.5(UBE3A):​c.*46dupA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00045 in 1,456,674 control chromosomes in the GnomAD database, including 1 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00048 (1 hom.)
• Consequence: UBE3A NM_130839.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00200
• Publications: 0 publications found

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: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 30 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UBE3A	NM_130839.5	c.*46dupA		3_prime_UTR_variant	Exon 13 of 13	ENST00000648336.2	NP_570854.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UBE3A	ENST00000648336.2	c.*46dupA		3_prime_UTR_variant	Exon 13 of 13		NM_130839.5	ENSP00000497572.2

Frequencies

GnomAD3 genomes AF: 0.000206 AC: 31 AN: 150310 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000171

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00133

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000210

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000445

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00152 AC: 126 AN: 82930 AF XY: 0.00132

Gnomad AFR exome AF: 0.00103

Gnomad AMR exome AF: 0.00458

Gnomad ASJ exome AF: 0.00122

Gnomad EAS exome AF: 0.000580

Gnomad FIN exome AF: 0.00227

Gnomad NFE exome AF: 0.00118

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000479 AC: 626 AN: 1306254 Hom.: 1 Cov.: 30 AF XY: 0.000500 AC XY: 321 AN XY: 641690

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000538 AC: 15 AN: 27892

American (AMR) AF: 0.00286 AC: 59 AN: 20644

Ashkenazi Jewish (ASJ) AF: 0.000885 AC: 19 AN: 21460

East Asian (EAS) AF: 0.000855 AC: 29 AN: 33910

South Asian (SAS) AF: 0.000796 AC: 53 AN: 66562

European-Finnish (FIN) AF: 0.00129 AC: 53 AN: 41084

Middle Eastern (MID) AF: 0.000542 AC: 2 AN: 3688

European-Non Finnish (NFE) AF: 0.000347 AC: 360 AN: 1037238

Other (OTH) AF: 0.000669 AC: 36 AN: 53776

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000199 AC: 30 AN: 150420 Hom.: 0 Cov.: 32 AF XY: 0.000163 AC XY: 12 AN XY: 73460

African (AFR) AF: 0.000170 AC: 7 AN: 41068

American (AMR) AF: 0.00126 AC: 19 AN: 15080

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3436

East Asian (EAS) AF: 0.00 AC: 0 AN: 5126

South Asian (SAS) AF: 0.000211 AC: 1 AN: 4750

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10260

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000445 AC: 3 AN: 67418

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.0000541 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.0020
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs368425414; hg19: chr15-25584237; COSMIC: COSV105081970; COSMIC: COSV105081970;