6-53073581-C-T

Variant summary

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

The NM_033480.3(FBXO9):​c.191C>T​(p.Ser64Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,458,610 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S64P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

FBXO9
NM_033480.3 missense

Scores

1
2
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.01
Variant links:
Genes affected
FBXO9 (HGNC:13588): (F-box protein 9) 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 at least 3 transcript variants diverging at the 5' terminus. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

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=0.1816701).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FBXO9NM_033480.3 linkc.191C>T p.Ser64Phe missense_variant Exon 3 of 13 ENST00000323557.12 NP_258441.1 Q9UK97-2
FBXO9NM_012347.4 linkc.221C>T p.Ser74Phe missense_variant Exon 2 of 12 NP_036479.1 Q9UK97-1
FBXO9NM_033481.3 linkc.89C>T p.Ser30Phe missense_variant Exon 3 of 13 NP_258442.2 Q9UK97-3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FBXO9ENST00000323557.12 linkc.191C>T p.Ser64Phe missense_variant Exon 3 of 13 1 NM_033480.3 ENSP00000326968.7 Q9UK97-2
FBXO9ENST00000244426.10 linkc.221C>T p.Ser74Phe missense_variant Exon 2 of 12 1 ENSP00000244426.6 Q9UK97-1
FBXO9ENST00000370939.7 linkc.89C>T p.Ser30Phe missense_variant Exon 3 of 13 1 ENSP00000359977.3 Q9UK97-3
FBXO9ENST00000498744.5 linkc.89C>T p.Ser30Phe missense_variant Exon 4 of 7 3 ENSP00000418858.1 C9IY65
FBXO9ENST00000473337.6 linkc.89C>T p.Ser30Phe missense_variant Exon 3 of 6 4 ENSP00000420536.1 C9JDZ9

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000412
AC:
1
AN:
242494
Hom.:
0
AF XY:
0.00000761
AC XY:
1
AN XY:
131374
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:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000915
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000343
AC:
5
AN:
1458610
Hom.:
0
Cov.:
31
AF XY:
0.00000276
AC XY:
2
AN XY:
725208
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:
0.00000450
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Dec 07, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.221C>T (p.S74F) alteration is located in exon 2 (coding exon 2) of the FBXO9 gene. This alteration results from a C to T substitution at nucleotide position 221, causing the serine (S) at amino acid position 74 to be replaced by a phenylalanine (F). 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
0.082
BayesDel_addAF
Benign
-0.041
T
BayesDel_noAF
Benign
-0.30
CADD
Benign
18
DANN
Benign
0.97
DEOGEN2
Benign
0.019
.;T;.;.;.;T
Eigen
Benign
-0.48
Eigen_PC
Benign
-0.40
FATHMM_MKL
Benign
0.68
D
LIST_S2
Benign
0.76
T;T;T;T;T;T
M_CAP
Benign
0.035
D
MetaRNN
Benign
0.18
T;T;T;T;T;T
MetaSVM
Benign
-0.90
T
MutationAssessor
Benign
0.90
.;.;.;.;.;L
PROVEAN
Pathogenic
-4.8
D;N;N;N;N;N
REVEL
Benign
0.21
Sift
Uncertain
0.020
D;D;D;D;D;D
Sift4G
Uncertain
0.010
D;T;T;T;T;T
Polyphen
0.0
.;.;.;B;.;B
Vest4
0.16, 0.17, 0.16
MutPred
0.28
.;.;.;.;.;Loss of phosphorylation at S74 (P = 0.0116);
MVP
0.44
MPC
0.49
ClinPred
0.19
T
GERP RS
5.7
Varity_R
0.056
gMVP
0.26

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.

Other links and lift over

dbSNP: rs371936172; hg19: chr6-52938379; COSMIC: COSV55054978; COSMIC: COSV55054978; API