Genetic Variant NM_130466.4:c.143G>T (chr12-109483694-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_130466.4(UBE3B):c.143G>T(p.Arg48Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,454,196 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

UBE3B
NM_130466.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.57

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.19194728).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UBE3B	NM_130466.4 link	c.143G>T	p.Arg48Leu	missense_variant	Exon 3 of 28	ENST00000342494.8	NP_569733.2	Q7Z3V4-1A0A024RBI2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UBE3B	ENST00000342494.8 link	c.143G>T	p.Arg48Leu	missense_variant	Exon 3 of 28	1	NM_130466.4	ENSP00000340596.3		Q7Z3V4-1
UBE3B	ENST00000449510.6 link	n.143G>T		non_coding_transcript_exon_variant	Exon 3 of 29	5		ENSP00000395802.2		Q7Z3V4-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1454196

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723256

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.0000333

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.28

T;.;T;T;.;.;T

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.91

FATHMM_MKL

Benign

0.42

LIST_S2

Uncertain

0.95

.;.;D;D;.;D;D

M_CAP

Uncertain

0.092

MetaRNN

Benign

0.19

T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

L;L;.;L;L;L;.

PrimateAI

Benign

0.25

PROVEAN

Uncertain

-2.9

D;D;D;D;D;D;D

REVEL

Benign

0.093

Sift

Uncertain

0.014

D;D;D;D;D;D;D

Sift4G

Uncertain

0.025

D;D;D;D;D;D;D

Polyphen

0.79

P;P;.;P;P;P;B

Vest4

0.53

MutPred

0.56

Loss of MoRF binding (P = 0.0179);Loss of MoRF binding (P = 0.0179);Loss of MoRF binding (P = 0.0179);Loss of MoRF binding (P = 0.0179);Loss of MoRF binding (P = 0.0179);Loss of MoRF binding (P = 0.0179);Loss of MoRF binding (P = 0.0179);

MVP

0.33

MPC

0.50

ClinPred

0.92

GERP RS

-0.60

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.16

gMVP

0.54

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over