rs141984760

chr15-25371110-C-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_130839.5(UBE3A):c.1064G>C(p.Ser355Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000867 in 1,614,130 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Synonymous variant affecting the same amino acid position (i.e. S355S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000088 (2 hom.)
• Consequence: UBE3A NM_130839.5 missense
• Clinical Significance: Benign reviewed by expert panel U:3 B:3
• Conservation: PhyloP100: 0.458

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 Benign. Variant got -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, UBE3A
• BP4: Computational evidence support a benign effect (MetaRNN=0.020141244).
• BP6: Variant 15-25371110-C-G is Benign according to our data. Variant chr15-25371110-C-G is described in ClinVar as [Benign]. Clinvar id is 156132.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS2: High AC in GnomAd at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UBE3A	NM_130839.5	c.1064G>C	p.Ser355Thr	missense_variant	6/13	ENST00000648336.2
SNHG14	NR_146177.1	n.18393-20486C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UBE3A	ENST00000648336.2	c.1064G>C	p.Ser355Thr	missense_variant	6/13		NM_130839.5	P1
SNHG14	ENST00000656420.1	n.5457-47678C>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0000788 AC: 12 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000143 AC: 36 AN: 251254 Hom.: 0 AF XY: 0.000191 AC XY: 26 AN XY: 135794

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000785

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000792

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000876 AC: 128 AN: 1461820 Hom.: 2 Cov.: 33 AF XY: 0.000110 AC XY: 80 AN XY: 727192

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000870

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000297

Gnomad4 OTH exome AF: 0.0000993

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152310 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8 AN XY: 74484

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00103

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.0000675 Hom.: 0

Bravo AF: 0.0000567

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000173 AC: 21

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Uncertain:3 Benign:3

Revision: reviewed by expert panel

Submissions by phenotype

Angelman syndrome Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 06, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Baylor Genetics	Feb 14, 2014	possible diagnosis of Angelman syndrome -
Benign, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Jun 30, 2022	The allele frequency of the c.1064G>C p.(Ser355Thr) variant in UBE3A (NM_130839.5) is 0.078% in the South Asian sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). In summary, the c.1064G>C p.(Ser355Thr) variant in UBE3A is classified as Benign based on the ACMG/AMP criteria (BA1). -

not provided Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2021	This variant is associated with the following publications: (PMID: 25212744) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2016	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 15, 2017

The p.S335T variant (also known as c.1004G>C), located in coding exon 3 of the UBE3A gene, results from a G to C substitution at nucleotide position 1004. The serine at codon 335 is replaced by threonine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.71
Cadd	Benign	12
Dann	Benign	0.78
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.89	D
M_CAP	Benign	0.0073	T
MetaRNN	Benign	0.020	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.41	T
Polyphen		0.018, 0.031	.;B;.;.;.;B;.;B;.;B;.;.;.;B;.
Vest4		0.19, 0.15, 0.13, 0.17, 0.13, 0.14, 0.15, 0.12
MVP		0.34
MPC		0.84
ClinPred		0.015	T
GERP RS		2.6
Varity_R		0.11
gMVP		0.29

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: rs141984760; hg19: chr15-25616257;