NM_130839.5:c.*4A>G

Variant names:

• chr15-25339133-T-C
• rs755581358
• NM_130839.5:c.*4A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

This summary comes from the ClinGen Evidence Repository: The c.*4A>G variant in UBE3A (NM_130838.2) is present in gnomAD v2.1.1 at a frequency of 0.0068% in the European (non-Finnish) sub population (no criteria met). In summary, the c.*4A>G variant in UBE3A is classified as Variant of Uncertain Significance based on the ACMG/AMP criteria (no criteria met). LINK:https://erepo.genome.network/evrepo/ui/classification/CA7435334/MONDO:0007113/032

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000076 (0 hom.)
• Consequence: UBE3A NM_130839.5 3_prime_UTR
• Clinical Significance: Uncertain significance reviewed by expert panel U:2 B:1
• Conservation: PhyloP100: 0.834
• 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: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_130839.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBE3A	NM_130839.5	MANE Select	c.*4A>G		3_prime_UTR	Exon 13 of 13	NP_570854.1	Q05086-3
	UBE3A	NM_000462.5		c.*4A>G		3_prime_UTR	Exon 14 of 14	NP_000453.2
	UBE3A	NM_001354505.1		c.*4A>G		3_prime_UTR	Exon 13 of 13	NP_001341434.1	Q05086-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBE3A	ENST00000648336.2	MANE Select	c.*4A>G		3_prime_UTR	Exon 13 of 13	ENSP00000497572.2	Q05086-3
	UBE3A	ENST00000566215.5	TSL:1	c.*4A>G		3_prime_UTR	Exon 15 of 15	ENSP00000457771.1	Q05086-2
	SNHG14	ENST00000424333.6	TSL:1	n.5766+60249T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000312 AC: 6 AN: 192226 AF XY: 0.00000958

Gnomad AFR exome AF: 0.00

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: 0.0000682

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000761 AC: 106 AN: 1393636 Hom.: 0 Cov.: 31 AF XY: 0.0000768 AC XY: 53 AN XY: 689814

African (AFR) AF: 0.0000328 AC: 1 AN: 30494

American (AMR) AF: 0.00 AC: 0 AN: 31886

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23358

East Asian (EAS) AF: 0.00 AC: 0 AN: 38516

South Asian (SAS) AF: 0.00 AC: 0 AN: 73664

European-Finnish (FIN) AF: 0.0000393 AC: 2 AN: 50920

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4792

European-Non Finnish (NFE) AF: 0.0000942 AC: 102 AN: 1082708

Other (OTH) AF: 0.0000175 AC: 1 AN: 57298

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152156 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74340

African (AFR) AF: 0.00 AC: 0 AN: 41446

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.0000283 Hom.: 0

Bravo AF: 0.0000302

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	1	-	Angelman syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	10
DANN	Benign	0.80
PhyloP100		0.83

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: rs755581358; hg19: chr15-25584280;