11-33755788-C-T

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

2
16

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]

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
FBXO3NM_012175.4 linkc.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
FBXO3ENST00000265651.8 linkc.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.:
32
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.:
31
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.:
32
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:
66
ESP6500EA
AF:
0.102
AC:
874
ExAC
AF:
0.0661
AC:
8029
Asia WGS
AF:
0.0170
AC:
59
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
T
BayesDel_noAF
Benign
-0.58
CADD
Benign
20
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
D
LIST_S2
Uncertain
0.87
D;D;D;D;D
MetaRNN
Benign
0.0018
T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-0.34
.;N;.;.;N
PrimateAI
Benign
0.46
T
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
T
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.

Other links and lift over

dbSNP: rs1402954; hg19: chr11-33777334; COSMIC: COSV55765514; COSMIC: COSV55765514; API