rs369853017

Positions:

• chr15-25375498-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM2 PP2 BP4_Strong BP6

The NM_130839.5(UBE3A):​c.328A>G​(p.Met110Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,614,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: UBE3A NM_130839.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.39

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:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), UBE3A. . Trascript score misZ 6.9443 (greater than threshold 3.09). GenCC has associacion of gene with Angelman syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0652785).
• BP6: Variant 15-25375498-T-C is Benign according to our data. Variant chr15-25375498-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 160222.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UBE3A	NM_130839.5	c.328A>G	p.Met110Val	missense_variant	5/13	ENST00000648336.2	NP_570854.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UBE3A	ENST00000648336.2	c.328A>G	p.Met110Val	missense_variant	5/13		NM_130839.5	ENSP00000497572.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152228 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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461822 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727206

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152228 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74370

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000113

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Angelman syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 12, 2021

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	13
DANN	Benign	0.88
DEOGEN2	Benign	0.16	.;.;.;.;.;.;.;.;.;T;.;.;.;T;T;.;T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.88	.;.;.;D;.;.;.;D;.;.;.;.;D;D;D;D;D
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.065	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.92	.;.;.;.;.;.;.;.;.;L;.;.;.;L;.;.;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.71	.;.;.;.;N;.;.;.;.;.;.;N;N;N;.;.;.
REVEL	Benign	0.047
Sift	Benign	0.98	.;.;.;.;T;.;.;.;.;.;.;T;T;T;.;.;.
Sift4G	Benign	0.36	.;.;.;.;.;T;.;.;.;.;.;.;.;T;.;T;.
Polyphen		0.0070, 0.0030	.;B;.;.;.;B;.;B;.;B;.;.;.;B;.;.;.
Vest4		0.21, 0.28, 0.24, 0.27, 0.24, 0.23, 0.20, 0.22
MVP		0.42
MPC		0.93
ClinPred		0.036	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.043
gMVP		0.45

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: rs369853017; hg19: chr15-25620645;