rs34670662

Variant names:

• chr15-25356877-T-C
• rs34670662
• NM_130839.5:c.1773A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_130839.5(UBE3A):​c.1773A>G​(p.Glu591Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00448 in 1,613,634 control chromosomes in the GnomAD database, including 303 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (161 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (142 hom.)
• Consequence: UBE3A NM_130839.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.227
• Publications: 5 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 15-25356877-T-C is Benign according to our data. Variant chr15-25356877-T-C is described in ClinVar as Benign. ClinVar VariationId is 96258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.227 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0822 is higher than 0.05.

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.1773A>G	p.Glu591Glu	synonymous	Exon 8 of 13	NP_570854.1	Q05086-3
	UBE3A	NM_000462.5		c.1782A>G	p.Glu594Glu	synonymous	Exon 9 of 14	NP_000453.2
	UBE3A	NM_001354505.1		c.1773A>G	p.Glu591Glu	synonymous	Exon 8 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.1773A>G	p.Glu591Glu	synonymous	Exon 8 of 13	ENSP00000497572.2	Q05086-3
	UBE3A	ENST00000566215.5	TSL:1	c.1713A>G	p.Glu571Glu	synonymous	Exon 10 of 15	ENSP00000457771.1	Q05086-2
	SNHG14	ENST00000424333.6	TSL:1	n.5767-61911T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0241 AC: 3665 AN: 152166 Hom.: 159 Cov.: 32

Gnomad AFR AF: 0.0846

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00700

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.0196

GnomAD2 exomes AF: 0.00620 AC: 1556 AN: 251128 AF XY: 0.00447

Gnomad AFR exome AF: 0.0848

Gnomad AMR exome AF: 0.00385

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.00344

GnomAD4 exome AF: 0.00243 AC: 3551 AN: 1461350 Hom.: 142 Cov.: 31 AF XY: 0.00209 AC XY: 1518 AN XY: 726990

African (AFR) AF: 0.0869 AC: 2908 AN: 33456

American (AMR) AF: 0.00436 AC: 195 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39592

South Asian (SAS) AF: 0.000197 AC: 17 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00555 AC: 32 AN: 5764

European-Non Finnish (NFE) AF: 0.0000846 AC: 94 AN: 1111706

Other (OTH) AF: 0.00505 AC: 305 AN: 60354

GnomAD4 genome AF: 0.0241 AC: 3674 AN: 152284 Hom.: 161 Cov.: 32 AF XY: 0.0230 AC XY: 1715 AN XY: 74470

African (AFR) AF: 0.0846 AC: 3514 AN: 41550

American (AMR) AF: 0.00700 AC: 107 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68016

Other (OTH) AF: 0.0194 AC: 41 AN: 2114

Alfa AF: 0.0132 Hom.: 51

Bravo AF: 0.0273

Asia WGS AF: 0.00520 AC: 19 AN: 3478

EpiCase AF: 0.000437

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	6.9
DANN	Benign	0.79
PhyloP100		0.23
PromoterAI		0.0017	Neutral
Mutation Taster		=99/1	polymorphism (auto)

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: rs34670662; hg19: chr15-25602024;