NM_130839.5:c.1269C>T

Variant names:

• chr15-25370905-G-A
• rs149506027
• NM_130839.5:c.1269C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP7 BA1

This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Asp423= variant in UBE3A is 0.18% in European (Non-Finnish) sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The silent p.Asp423= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP7). In summary, the p.Asp423= variant in UBE3A is classified as benign based on the ACMG/AMP criteria (BA1, BP7). LINK:https://erepo.genome.network/evrepo/ui/classification/CA149398/MONDO:0007113/016

• Frequency:
  • Genomes: 𝑓 0.0013 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (7 hom.)
• Consequence: UBE3A NM_130839.5 synonymous
• Clinical Significance: Benign reviewed by expert panel U:1 B:8
• Conservation: PhyloP100: 2.52
• Publications: 3 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 -9 ACMG points.

• BP7: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

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.1269C>T	p.Asp423Asp	synonymous	Exon 6 of 13	NP_570854.1
	UBE3A	NM_000462.5		c.1278C>T	p.Asp426Asp	synonymous	Exon 7 of 14	NP_000453.2
	UBE3A	NM_001354505.1		c.1269C>T	p.Asp423Asp	synonymous	Exon 6 of 13	NP_001341434.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBE3A	ENST00000648336.2	MANE Select	c.1269C>T	p.Asp423Asp	synonymous	Exon 6 of 13	ENSP00000497572.2
	UBE3A	ENST00000566215.5	TSL:1	c.1209C>T	p.Asp403Asp	synonymous	Exon 8 of 15	ENSP00000457771.1
	SNHG14	ENST00000424333.6	TSL:1	n.5767-47883G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00129 AC: 196 AN: 152072 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00215

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00111 AC: 279 AN: 250778 AF XY: 0.00121

Gnomad AFR exome AF: 0.000559

Gnomad AMR exome AF: 0.000406

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00176

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.00181 AC: 2645 AN: 1461802 Hom.: 7 Cov.: 32 AF XY: 0.00183 AC XY: 1334 AN XY: 727196

African (AFR) AF: 0.000269 AC: 9 AN: 33480

American (AMR) AF: 0.000335 AC: 15 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00162 AC: 140 AN: 86246

European-Finnish (FIN) AF: 0.000243 AC: 13 AN: 53402

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00213 AC: 2363 AN: 1111972

Other (OTH) AF: 0.00166 AC: 100 AN: 60392

GnomAD4 genome AF: 0.00129 AC: 196 AN: 152190 Hom.: 2 Cov.: 32 AF XY: 0.00125 AC XY: 93 AN XY: 74406

African (AFR) AF: 0.000289 AC: 12 AN: 41520

American (AMR) AF: 0.00157 AC: 24 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4816

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00215 AC: 146 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00149 Hom.: 1

Bravo AF: 0.00130

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	2	Angelman syndrome (3)
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	6.7
DANN	Benign	0.88
PhyloP100		2.5
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
Mutation Taster		=96/4	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: rs149506027; hg19: chr15-25616052;