15-25375696-C-T

Variant names:

• chr15-25375696-C-T
• rs1555403204
• NM_130839.5:c.130G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 5P and 2B. PM1 PM2 PP2 BP4_Moderate

The NM_130839.5(UBE3A):​c.130G>A​(p.Glu44Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E44A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: UBE3A NM_130839.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.80
• 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 3 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_130839.5
• 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=0.2228167).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBE3A	NM_130839.5	MANE Select	c.130G>A	p.Glu44Lys	missense	Exon 5 of 13	NP_570854.1
	UBE3A	NM_000462.5		c.139G>A	p.Glu47Lys	missense	Exon 6 of 14	NP_000453.2
	UBE3A	NM_001354505.1		c.130G>A	p.Glu44Lys	missense	Exon 5 of 13	NP_001341434.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBE3A	ENST00000648336.2	MANE Select	c.130G>A	p.Glu44Lys	missense	Exon 5 of 13	ENSP00000497572.2
	UBE3A	ENST00000566215.5	TSL:1	c.70G>A	p.Glu24Lys	missense	Exon 7 of 15	ENSP00000457771.1
	SNHG14	ENST00000424333.6	TSL:1	n.5767-43092C>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

May 09, 2017

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Uncertain:1

Jun 16, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.071	T
Eigen	Benign	0.062
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
PhyloP100		4.8
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.45	N
REVEL	Benign	0.15
Sift	Benign	0.77	T
Sift4G	Benign	0.86	T
Polyphen		0.34	B
Vest4		0.54
MutPred		0.38		Gain of methylation at E47 (P = 0.0114)
MVP		0.32
MPC		1.0
ClinPred		0.98	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.58
gMVP		0.46

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: rs1555403204; hg19: chr15-25620843; COSMIC: COSV51671252; COSMIC: COSV51671252;