15-25339114-G-T

Variant names:

• chr15-25339114-G-T
• rs955490436
• NM_130839.5:c.*23C>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

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
• 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 -6 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UBE3A	NM_130839.5	c.*23C>A		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.*23C>A		3_prime_UTR_variant	Exon 13 of 13		NM_130839.5	ENSP00000497572.2

Frequencies

GnomAD3 genomes AF: 0.000169 AC: 23 AN: 135732 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.0184 AC: 2035 AN: 110544 AF XY: 0.0166

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 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

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

African (AFR) AF: 0.0115 AC: 299 AN: 25960

American (AMR) AF: 0.0298 AC: 554 AN: 18596

Ashkenazi Jewish (ASJ) AF: 0.0155 AC: 303 AN: 19610

East Asian (EAS) AF: 0.0232 AC: 745 AN: 32110

South Asian (SAS) AF: 0.0376 AC: 1829 AN: 48662

European-Finnish (FIN) AF: 0.00650 AC: 271 AN: 41704

Middle Eastern (MID) AF: 0.0111 AC: 42 AN: 3792

European-Non Finnish (NFE) AF: 0.00594 AC: 5819 AN: 980130

Other (OTH) AF: 0.0105 AC: 517 AN: 49432

⚠️ 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 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

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

African (AFR) AF: 0.0000814 AC: 3 AN: 36856

American (AMR) AF: 0.000218 AC: 3 AN: 13760

Ashkenazi Jewish (ASJ) AF: 0.000320 AC: 1 AN: 3128

East Asian (EAS) AF: 0.00 AC: 0 AN: 4842

South Asian (SAS) AF: 0.000233 AC: 1 AN: 4288

European-Finnish (FIN) AF: 0.000932 AC: 8 AN: 8584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 266

European-Non Finnish (NFE) AF: 0.000114 AC: 7 AN: 61380

Other (OTH) AF: 0.00 AC: 0 AN: 1904

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Mar 06, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.41
DANN	Benign	0.35
PhyloP100		0.0

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: rs955490436; hg19: chr15-25584261;