Genetic Variant FBXO3:p.Val221Ile (chr11-33755788-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

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

The NM_012175.4(FBXO3):c.661G>A(p.Val221Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0797 in 1,613,120 control chromosomes in the GnomAD database, including 5,953 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.064 ( 460 hom., cov: 32)

Exomes 𝑓: 0.081 ( 5493 hom. )

Consequence

FBXO3
NM_012175.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 5.86

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:

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=0.0018072724).

BP6

Variant 11-33755788-C-T is Benign according to our data. Variant chr11-33755788-C-T is described in ClinVar as [Benign]. Clinvar id is 1278752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.096 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXO3	NM_012175.4 link	c.661G>A	p.Val221Ile	missense_variant	Exon 5 of 11	ENST00000265651.8	NP_036307.2	Q9UK99-1Q49AF1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBXO3	ENST00000265651.8 link	c.661G>A	p.Val221Ile	missense_variant	Exon 5 of 11	1	NM_012175.4	ENSP00000265651.3		Q9UK99-1

Frequencies

GnomAD3 genomes

AF:

0.0642

AC:

9775

AN:

152158

Hom.:

460

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0163

Gnomad AMI

AF:

0.0614

Gnomad AMR

AF:

0.0737

Gnomad ASJ

AF:

0.140

Gnomad EAS

AF:

0.000384

Gnomad SAS

AF:

0.0215

Gnomad FIN

AF:

0.0468

Gnomad MID

AF:

0.0791

Gnomad NFE

AF:

0.0979

Gnomad OTH

AF:

0.0716

GnomAD3 exomes

AF:

0.0661

AC:

16608

AN:

251280

Hom.:

749

AF XY:

0.0668

AC XY:

9066

AN XY:

135796

show subpopulations

Gnomad AFR exome

AF:

0.0144

Gnomad AMR exome

AF:

0.0499

Gnomad ASJ exome

AF:

0.116

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.0212

Gnomad FIN exome

AF:

0.0482

Gnomad NFE exome

AF:

0.0991

Gnomad OTH exome

AF:

0.0875

GnomAD4 exome

AF:

0.0814

AC:

118853

AN:

1460844

Hom.:

5493

Cov.:

AF XY:

0.0805

AC XY:

58523

AN XY:

726802

show subpopulations

Gnomad4 AFR exome

AF:

0.0137

Gnomad4 AMR exome

AF:

0.0518

Gnomad4 ASJ exome

AF:

0.120

Gnomad4 EAS exome

AF:

0.000176

Gnomad4 SAS exome

AF:

0.0225

Gnomad4 FIN exome

AF:

0.0517

Gnomad4 NFE exome

AF:

0.0927

Gnomad4 OTH exome

AF:

0.0789

GnomAD4 genome

AF:

0.0642

AC:

9778

AN:

152276

Hom.:

460

Cov.:

AF XY:

0.0611

AC XY:

4546

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.0162

Gnomad4 AMR

AF:

0.0736

Gnomad4 ASJ

AF:

0.140

Gnomad4 EAS

AF:

0.000385

Gnomad4 SAS

AF:

0.0216

Gnomad4 FIN

AF:

0.0468

Gnomad4 NFE

AF:

0.0979

Gnomad4 OTH

AF:

0.0709

Alfa

AF:

0.0933

Hom.:

1855

Bravo

AF:

0.0645

TwinsUK

AF:

0.0874

AC:

324

ALSPAC

AF:

0.0807

AC:

311

ESP6500AA

AF:

0.0150

AC:

ESP6500EA

AF:

0.102

AC:

874

ExAC

AF:

0.0661

AC:

8029

Asia WGS

AF:

0.0170

AC:

AN:

3478

EpiCase

AF:

0.101

EpiControl

AF:

0.108

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 15, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 30448480) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Benign

0.61

DEOGEN2

Benign

0.0080

T;T;.;T;.

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.0066

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.87

D;D;D;D;D

MetaRNN

Benign

0.0018

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.34

.;N;.;.;N

PrimateAI

Benign

0.46

PROVEAN

Benign

0.040

N;N;N;N;N

REVEL

Benign

0.13

Sift

Benign

0.83

T;T;T;T;T

Sift4G

Benign

1.0

T;T;T;T;T

Polyphen

0.0010, 0.0020

.;B;B;.;B

Vest4

0.029

MPC

0.47

ClinPred

0.024

GERP RS

4.9

Varity_R

0.043

gMVP

0.26

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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