rs587784528

chr15-25339147-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PP2 PP3_Moderate PP5

The NM_130839.5(UBE3A):c.2609G>A(p.Gly870Asp) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic 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: 6.9e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: UBE3A NM_130839.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 7.91

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

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a domain HECT (size 99) in uniprot entity UBE3A_HUMAN there are 16 pathogenic changes around while only 1 benign (94%) in NM_130839.5
• PP2: Missense variant where missense usually causes diseases, UBE3A
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.917
• PP5: Variant 15-25339147-C-T is Pathogenic according to our data. Variant chr15-25339147-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 160221.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}. Variant chr15-25339147-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UBE3A	NM_130839.5	c.2609G>A	p.Gly870Asp	missense_variant	13/13	ENST00000648336.2
SNHG14	NR_146177.1	n.18393-52449C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UBE3A	ENST00000648336.2	c.2609G>A	p.Gly870Asp	missense_variant	13/13		NM_130839.5	P1
SNHG14	ENST00000656420.1	n.5456+60263C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.92e-7 AC: 1 AN: 1444144 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 717718

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000191

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Angelman syndrome Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Lab, CHRU Brest	-	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jan 15, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.24
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Benign	0.12	T;.;.;.;.;.;.;.;.;T;.;.;.;.;T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;.;.;.;.;.;.;D;.;.;.;.;D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.31	T
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.91	D
Polyphen		1.0	.;.;D;.;.;D;.;D;.;D;.;.;.;.;D
Vest4		0.91, 0.79, 0.74, 0.80, 0.87, 0.88, 0.90
MutPred		0.75		.;.;.;.;.;.;.;.;.;Loss of catalytic residue at G873 (P = 0.0056);.;.;.;.;Loss of catalytic residue at G873 (P = 0.0056);
MVP		0.72
MPC		2.3
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.96
gMVP		0.98

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

Publications

LitVar

Other links and lift over

dbSNP: rs587784528; hg19: chr15-25584294;