rs587784523

Variant names:

• chr15-25355930-T-C
• rs587784523
• NM_130839.5:c.2086A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4 BP6

The NM_130839.5(UBE3A):​c.2086A>G​(p.Asn696Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,342 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: UBE3A NM_130839.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.16
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the UBE3A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 44 curated pathogenic missense variants (we use a threshold of 10). The gene has 8 curated benign missense variants. Trascript score misZ: 6.9443 (above the threshold of 3.09). GenCC associations: The gene is linked to Angelman syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.388301).
• BP6: Variant 15-25355930-T-C is Benign according to our data. Variant chr15-25355930-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 160216.

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.2086A>G	p.Asn696Asp	missense	Exon 9 of 13	NP_570854.1	Q05086-3
	UBE3A	NM_000462.5		c.2095A>G	p.Asn699Asp	missense	Exon 10 of 14	NP_000453.2
	UBE3A	NM_001354505.1		c.2086A>G	p.Asn696Asp	missense	Exon 9 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.2086A>G	p.Asn696Asp	missense	Exon 9 of 13	ENSP00000497572.2	Q05086-3
	UBE3A	ENST00000566215.5	TSL:1	c.2026A>G	p.Asn676Asp	missense	Exon 11 of 15	ENSP00000457771.1	Q05086-2
	SNHG14	ENST00000424333.6	TSL:1	n.5767-62858T>C		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461342 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726982

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39596

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5690

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111740

Other (OTH) AF: 0.0000166 AC: 1 AN: 60368

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Angelman syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.086
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	0.94	L
PhyloP100		2.2
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.25
Sift	Benign	0.17	T
Sift4G	Benign	0.32	T
Polyphen		0.0020	B
Vest4		0.31
MutPred		0.65		Gain of sheet (P = 0.0827)
MVP		0.59
MPC		1.0
ClinPred		0.62	D
GERP RS		4.6
PromoterAI		0.015	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.57
gMVP		0.63
Mutation Taster		=65/35	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: rs587784523; hg19: chr15-25601077;