Genetic Variant FBXO3:p.Arg466Cys (chr11-33741928-G-A) – 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_012175.4(FBXO3):c.1396C>T(p.Arg466Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,170 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R466H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

FBXO3
NM_012175.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.97

Variant links:

Genes affected

FBXO3 (HGNC:13582): (F-box protein 3) This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of the ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbxs class. Alternative splicing of this gene generates 2 transcript variants diverging at the 3' end. [provided by RefSeq, Jul 2008]

FBXO3 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=0.24959564).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXO3	NM_012175.4 link	c.1396C>T	p.Arg466Cys	missense_variant	Exon 11 of 11	ENST00000265651.8	NP_036307.2	Q9UK99-1Q49AF1
FBXO3	NM_033406.4 link	c.*5193C>T		3_prime_UTR_variant	Exon 10 of 10		NP_208385.1	Q9UK99-2Q49AF1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBXO3	ENST00000265651.8 link	c.1396C>T	p.Arg466Cys	missense_variant	Exon 11 of 11	1	NM_012175.4	ENSP00000265651.3		Q9UK99-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

250234

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135274

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000329

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74334

show subpopulations

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

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 03, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1396C>T (p.R466C) alteration is located in exon 11 (coding exon 11) of the FBXO3 gene. This alteration results from a C to T substitution at nucleotide position 1396, causing the arginine (R) at amino acid position 466 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.024

BayesDel_noAF

Benign

-0.27

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.014

T;T;.;.

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.78

LIST_S2

Uncertain

0.89

D;D;.;D

M_CAP

Benign

0.023

MetaRNN

Benign

0.25

T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.69

.;N;.;.

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-0.62

N;N;N;N

REVEL

Benign

0.17

Sift

Uncertain

0.0020

D;D;D;D

Sift4G

Uncertain

0.0030

D;D;D;D

Polyphen

1.0

.;D;.;.

Vest4

0.50

MutPred

0.23

.;Gain of helix (P = 0.132);.;.;

MVP

0.39

MPC

0.79

ClinPred

0.64

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.13

gMVP

0.31

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