15-25339138-T-C

Variant names:

• chr15-25339138-T-C
• rs76794400
• NM_130839.5:c.2618A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_130839.5(UBE3A):​c.2618A>G​(p.Ter873Ter) variant causes a stop retained change. The variant allele was found at a frequency of 0.00458 in 1,585,894 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0047 (22 hom.)
• Consequence: UBE3A NM_130839.5 stop_retained
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 4.03
• Publications: 6 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 15-25339138-T-C is Benign according to our data. Variant chr15-25339138-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 96262.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 465 AD gene.

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.2618A>G	p.Ter873Ter	stop_retained	Exon 13 of 13	NP_570854.1	Q05086-3
	UBE3A	NM_000462.5		c.2627A>G	p.Ter876Ter	stop_retained	Exon 14 of 14	NP_000453.2
	UBE3A	NM_001354505.1		c.2618A>G	p.Ter873Ter	stop_retained	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.2618A>G	p.Ter873Ter	stop_retained	Exon 13 of 13	ENSP00000497572.2	Q05086-3
	UBE3A	ENST00000566215.5	TSL:1	c.2558A>G	p.Ter853Ter	stop_retained	Exon 15 of 15	ENSP00000457771.1	Q05086-2
	SNHG14	ENST00000424333.6	TSL:1	n.5766+60254T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00306 AC: 466 AN: 152140 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00254

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00510

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00304 AC: 673 AN: 221058 AF XY: 0.00317

Gnomad AFR exome AF: 0.000477

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00339

Gnomad NFE exome AF: 0.00558

Gnomad OTH exome AF: 0.00313

GnomAD4 exome AF: 0.00474 AC: 6793 AN: 1433636 Hom.: 22 Cov.: 31 AF XY: 0.00462 AC XY: 3286 AN XY: 711722

African (AFR) AF: 0.000558 AC: 18 AN: 32232

American (AMR) AF: 0.00110 AC: 44 AN: 40064

Ashkenazi Jewish (ASJ) AF: 0.000160 AC: 4 AN: 25046

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39326

South Asian (SAS) AF: 0.00 AC: 0 AN: 80740

European-Finnish (FIN) AF: 0.00432 AC: 225 AN: 52142

Middle Eastern (MID) AF: 0.000990 AC: 5 AN: 5050

European-Non Finnish (NFE) AF: 0.00573 AC: 6307 AN: 1099874

Other (OTH) AF: 0.00319 AC: 189 AN: 59162

GnomAD4 genome AF: 0.00305 AC: 465 AN: 152258 Hom.: 2 Cov.: 32 AF XY: 0.00291 AC XY: 217 AN XY: 74464

African (AFR) AF: 0.00123 AC: 51 AN: 41556

American (AMR) AF: 0.00222 AC: 34 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00254 AC: 27 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00509 AC: 346 AN: 67996

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.00414 Hom.: 0

Bravo AF: 0.00277

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	not provided (4)
-	-	2	Angelman syndrome (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	UBE3A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	12
DANN	Benign	0.90
PhyloP100		4.0
Mutation Taster		=88/12	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: rs76794400; hg19: chr15-25584285;