rs7298565

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_130466.4(UBE3B):c.1037G>A(p.Arg346Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.522 in 1,611,796 control chromosomes in the GnomAD database, including 224,515 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.57 ( 25833 hom., cov: 32)

Exomes 𝑓: 0.52 ( 198682 hom. )

Consequence

UBE3B
NM_130466.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 7.26

Variant links:

Genes affected

UBE3B (HGNC:13478): (ubiquitin protein ligase E3B) The modification of proteins with ubiquitin is an important cellular mechanism for targeting abnormal or short-lived proteins for degradation. Ubiquitination involves at least three classes of enzymes: E1 ubiquitin-activating enzymes, E2 ubiquitin-conjugating enzymes, and E3 ubiquitin-protein ligases. This gene encodes a member of the E3 ubiquitin-conjugating enzyme family which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme and transfers the ubiquitin to the targeted substrates. A HECT (homology to E6-AP C-terminus) domain in the C-terminus of the longer isoform of this protein is the catalytic site of ubiquitin transfer and forms a complex with E2 conjugases. Shorter isoforms of this protein which lack the C-terminal HECT domain are therefore unlikely to bind E2 enzymes. Alternatively spliced transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2012]

UBE3B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.9271438E-6).

BP6

Variant 12-109499729-G-A is Benign according to our data. Variant chr12-109499729-G-A is described in ClinVar as [Benign]. Clinvar id is 1600613.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-109499729-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.729 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UBE3B	NM_130466.4 linkuse as main transcript	c.1037G>A	p.Arg346Gln	missense_variant	12/28	ENST00000342494.8	NP_569733.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UBE3B	ENST00000342494.8 linkuse as main transcript	c.1037G>A	p.Arg346Gln	missense_variant	12/28	1	NM_130466.4	ENSP00000340596	P1	Q7Z3V4-1
UBE3B	ENST00000434735.6 linkuse as main transcript	c.1037G>A	p.Arg346Gln	missense_variant	12/28	1		ENSP00000391529	P1	Q7Z3V4-1
UBE3B	ENST00000539599.5 linkuse as main transcript	c.1037G>A	p.Arg346Gln	missense_variant	11/23	1		ENSP00000443131
UBE3B	ENST00000449510.6 linkuse as main transcript	c.1037G>A	p.Arg346Gln	missense_variant, NMD_transcript_variant	12/29	5		ENSP00000395802		Q7Z3V4-2

Frequencies

GnomAD3 genomes

AF:

0.570

AC:

86593

AN:

151902

Hom.:

25784

Cov.:

show subpopulations

Gnomad AFR

AF:

0.735

Gnomad AMI

AF:

0.588

Gnomad AMR

AF:

0.503

Gnomad ASJ

AF:

0.533

Gnomad EAS

AF:

0.296

Gnomad SAS

AF:

0.389

Gnomad FIN

AF:

0.464

Gnomad MID

AF:

0.563

Gnomad NFE

AF:

0.536

Gnomad OTH

AF:

0.583

GnomAD3 exomes

AF:

0.501

AC:

125037

AN:

249666

Hom.:

32664

AF XY:

0.497

AC XY:

67070

AN XY:

134976

show subpopulations

Gnomad AFR exome

AF:

0.745

Gnomad AMR exome

AF:

0.454

Gnomad ASJ exome

AF:

0.553

Gnomad EAS exome

AF:

0.293

Gnomad SAS exome

AF:

0.415

Gnomad FIN exome

AF:

0.467

Gnomad NFE exome

AF:

0.538

Gnomad OTH exome

AF:

0.511

GnomAD4 exome

AF:

0.517

AC:

755039

AN:

1459774

Hom.:

198682

Cov.:

AF XY:

0.515

AC XY:

374028

AN XY:

726222

show subpopulations

Gnomad4 AFR exome

AF:

0.740

Gnomad4 AMR exome

AF:

0.467

Gnomad4 ASJ exome

AF:

0.549

Gnomad4 EAS exome

AF:

0.297

Gnomad4 SAS exome

AF:

0.418

Gnomad4 FIN exome

AF:

0.469

Gnomad4 NFE exome

AF:

0.529

Gnomad4 OTH exome

AF:

0.519

GnomAD4 genome

AF:

0.570

AC:

86706

AN:

152022

Hom.:

25833

Cov.:

AF XY:

0.561

AC XY:

41664

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.735

Gnomad4 AMR

AF:

0.503

Gnomad4 ASJ

AF:

0.533

Gnomad4 EAS

AF:

0.296

Gnomad4 SAS

AF:

0.389

Gnomad4 FIN

AF:

0.464

Gnomad4 NFE

AF:

0.536

Gnomad4 OTH

AF:

0.583

Alfa

AF:

0.542

Hom.:

59626

Bravo

AF:

0.584

TwinsUK

AF:

0.525

AC:

1947

ALSPAC

AF:

0.510

AC:

1964

ESP6500AA

AF:

0.731

AC:

3222

ESP6500EA

AF:

0.532

AC:

4578

ExAC

AF:

0.510

AC:

61878

Asia WGS

AF:

0.388

AC:

1349

AN:

3478

EpiCase

AF:

0.555

EpiControl

AF:

0.548

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Oculocerebrofacial syndrome, Kaufman type

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.053

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Benign

0.36

DEOGEN2

Benign

0.030

T;T;T

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.28

LIST_S2

Uncertain

0.87

.;D;D

MetaRNN

Benign

0.0000019

T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-2.5

N;.;N

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Uncertain

0.71

PROVEAN

Benign

1.3

N;N;N

REVEL

Benign

0.13

Sift

Benign

1.0

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

B;.;B

Vest4

0.14

MPC

0.32

ClinPred

0.041

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.085

gMVP

0.087

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over