15-25371582-C-T

Variant names:

• chr15-25371582-C-T
• rs147145506
• NM_130839.5:c.592G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_130839.5(UBE3A):​c.592G>A​(p.Ala198Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0163 in 1,614,158 control chromosomes in the GnomAD database, including 289 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A198S) has been classified as Uncertain significance. The gene UBE3A is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.011 (15 hom., cov: 32)
  • Exomes 𝑓: 0.017 (274 hom.)
• Consequence: UBE3A NM_130839.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 3.02
• Publications: 21 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: Benign. The variant received -19 ACMG points.

• 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=0.005845487).
• BP6: Variant 15-25371582-C-T is Benign according to our data. Variant chr15-25371582-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 96265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0112 (1705/152296) while in subpopulation NFE AF = 0.0197 (1343/68016). AF 95% confidence interval is 0.0189. There are 15 homozygotes in GnomAd4. There are 762 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1705 AD gene.

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.592G>A	p.Ala198Thr	missense	Exon 6 of 13	NP_570854.1	Q05086-3
	UBE3A	NM_000462.5		c.601G>A	p.Ala201Thr	missense	Exon 7 of 14	NP_000453.2
	UBE3A	NM_001354505.1		c.592G>A	p.Ala198Thr	missense	Exon 6 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.592G>A	p.Ala198Thr	missense	Exon 6 of 13	ENSP00000497572.2	Q05086-3
	UBE3A	ENST00000566215.5	TSL:1	c.532G>A	p.Ala178Thr	missense	Exon 8 of 15	ENSP00000457771.1	Q05086-2
	SNHG14	ENST00000424333.6	TSL:1	n.5767-47206C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0112 AC: 1705 AN: 152178 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.00282

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00727

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00973

Gnomad FIN AF: 0.00527

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0197

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.0117 AC: 2940 AN: 251406 AF XY: 0.0120

Gnomad AFR exome AF: 0.00271

Gnomad AMR exome AF: 0.00523

Gnomad ASJ exome AF: 0.00198

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00693

Gnomad NFE exome AF: 0.0193

Gnomad OTH exome AF: 0.0106

GnomAD4 exome AF: 0.0169 AC: 24683 AN: 1461862 Hom.: 274 Cov.: 33 AF XY: 0.0166 AC XY: 12056 AN XY: 727230

African (AFR) AF: 0.00254 AC: 85 AN: 33480

American (AMR) AF: 0.00534 AC: 239 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00233 AC: 61 AN: 26134

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39694

South Asian (SAS) AF: 0.00912 AC: 787 AN: 86256

European-Finnish (FIN) AF: 0.00876 AC: 468 AN: 53418

Middle Eastern (MID) AF: 0.00468 AC: 27 AN: 5768

European-Non Finnish (NFE) AF: 0.0199 AC: 22077 AN: 1111994

Other (OTH) AF: 0.0155 AC: 934 AN: 60394

GnomAD4 genome AF: 0.0112 AC: 1705 AN: 152296 Hom.: 15 Cov.: 32 AF XY: 0.0102 AC XY: 762 AN XY: 74478

African (AFR) AF: 0.00281 AC: 117 AN: 41570

American (AMR) AF: 0.00726 AC: 111 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00974 AC: 47 AN: 4826

European-Finnish (FIN) AF: 0.00527 AC: 56 AN: 10622

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0197 AC: 1343 AN: 68016

Other (OTH) AF: 0.0114 AC: 24 AN: 2114

Alfa AF: 0.0151 Hom.: 40

Bravo AF: 0.0109

TwinsUK AF: 0.0208 AC: 77

ALSPAC AF: 0.0195 AC: 75

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.0186 AC: 160

ExAC AF: 0.0123 AC: 1498

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.0190

EpiControl AF: 0.0162

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	1	Angelman syndrome (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)
-	-	1	UBE3A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.20
Eigen_PC	Benign	0.064
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0058	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.14	N
PhyloP100		3.0
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.037
Sift	Benign	0.48	T
Sift4G	Benign	0.56	T
Polyphen		0.0	B
Vest4		0.089
MPC		0.89
ClinPred		0.0082	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.068
gMVP		0.21
Mutation Taster		=100/0	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: rs147145506; hg19: chr15-25616729; COSMIC: COSV107226566; COSMIC: COSV107226566;