rs745340054

Variant names:

• chr15-25339124-GT-G
• rs745340054
• NM_130839.5:c.*12delA

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_130839.5(UBE3A):​c.*12delA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000157 in 1,399,994 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: UBE3A NM_130839.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.255
• 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.

• BP6: Variant 15-25339124-GT-G is Benign according to our data. Variant chr15-25339124-GT-G is described in ClinVar as [Likely_benign]. Clinvar id is 1250412.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UBE3A	NM_130839.5	c.*12delA		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.*12delA		3_prime_UTR_variant	Exon 13 of 13		NM_130839.5	ENSP00000497572.2

Frequencies

GnomAD3 genomes AF: 0.000114 AC: 15 AN: 131938 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000398

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000554

GnomAD2 exomes AF: 0.0000306 AC: 4 AN: 130792 AF XY: 0.0000137

Gnomad AFR exome AF: 0.000490

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000552 AC: 7 AN: 1268056 Hom.: 0 Cov.: 31 AF XY: 0.00000484 AC XY: 3 AN XY: 619280

African (AFR) AF: 0.000149 AC: 4 AN: 26876

American (AMR) AF: 0.00 AC: 0 AN: 22356

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20722

East Asian (EAS) AF: 0.00 AC: 0 AN: 33720

South Asian (SAS) AF: 0.00 AC: 0 AN: 51642

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43492

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4140

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1013730

Other (OTH) AF: 0.0000584 AC: 3 AN: 51378

GnomAD4 genome AF: 0.000114 AC: 15 AN: 131938 Hom.: 0 Cov.: 32 AF XY: 0.0000939 AC XY: 6 AN XY: 63886

African (AFR) AF: 0.000398 AC: 14 AN: 35138

American (AMR) AF: 0.00 AC: 0 AN: 13220

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3106

East Asian (EAS) AF: 0.00 AC: 0 AN: 4656

South Asian (SAS) AF: 0.00 AC: 0 AN: 4114

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8502

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 278

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 60322

Other (OTH) AF: 0.000554 AC: 1 AN: 1806

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000110

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jan 30, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.26

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: rs745340054; hg19: chr15-25584271;