NM_130839.5:c.62T>C

Variant names:

• chr15-25405461-A-G
• rs587780577
• NM_130839.5:c.62T>C

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM6 PVS1 PP4 PP1 PM2_Supporting PS4_Moderate

This summary comes from the ClinGen Evidence Repository: The p.M1? variant in UBE3A is predicted to cause a truncated or absent protein by altering the start codon of the coding sequence in a UBE3A where loss-of-function is an established disease mechanism. Pathogenic variants affecting the start site have been described in affected patients (PVS1). The p.M1? variant has been observed in 3 other individuals with Angelman syndrome (PMID 29737008, 25212744) (PS4_Moderate). The p.M1? variant in UBE3A is absent from gnomAD (PM2_Supporting). The p.M1? variant in UBE3A has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with Angelman syndrome (PMID 29737008) (PM6). The variant has been reported to segregate in two informative meioses (PP1). The p.M1? variant in UBE3A has been reported in an individual with a clinical phenotype suggestive of Angelman syndrome (PMID 29737008, 25212744) (PP4). In summary, the p.M1? variant in UBE3A is classified as pathogenic for Angelman syndrome based on the ACMG/AMP criteria (PVS1, PS4_moderate, PM2_supporting, PM6, PP1, PP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA333472/MONDO:0007113/016

• Frequency: Genomes: not found (cov: 32)
• Consequence: UBE3A NM_130839.5 missense, splice_region
• Scores: Splicing: ADA: 0.9174
• Clinical Significance: Pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 5.67
• 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

Specifications for UBE3A are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: 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.62T>C	p.Met21Thr	missense splice_region	Exon 4 of 13	NP_570854.1	Q05086-3
	UBE3A	NM_000462.5		c.71T>C	p.Met24Thr	missense splice_region	Exon 5 of 14	NP_000453.2
	UBE3A	NM_001354505.1		c.62T>C	p.Met21Thr	missense splice_region	Exon 4 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.62T>C	p.Met21Thr	missense splice_region	Exon 4 of 13	ENSP00000497572.2	Q05086-3
	UBE3A	ENST00000566215.5	TSL:1	c.2T>C	p.Met1?	start_lost splice_region	Exon 6 of 15	ENSP00000457771.1	Q05086-2
	SNHG14	ENST00000424333.6	TSL:1	n.5767-13327A>G		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	Angelman syndrome (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.030	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		5.7
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.22
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.0	B
Vest4		0.95
MutPred		0.39		Gain of phosphorylation at M24 (P = 0.0102)
MVP		0.53
MPC		1.1
ClinPred		0.91	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.55
gMVP		0.61
Mutation Taster		=10/190	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.92
dbscSNV1_RF	Pathogenic	0.78
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: rs587780577; hg19: chr15-25650608;