6-53097821-G-C

Variant names:

Variant summary

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

The NM_033480.3(FBXO9):c.1305G>C(p.Arg435Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000188 in 1,598,190 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

FBXO9
NM_033480.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.17

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]

FBXO9 links:

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=0.08496383).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXO9	NM_033480.3 link	c.1305G>C	p.Arg435Ser	missense_variant	Exon 13 of 13	ENST00000323557.12	NP_258441.1	Q9UK97-2
FBXO9	NM_012347.4 link	c.1335G>C	p.Arg445Ser	missense_variant	Exon 12 of 12		NP_036479.1	Q9UK97-1
FBXO9	NM_033481.3 link	c.1203G>C	p.Arg401Ser	missense_variant	Exon 13 of 13		NP_258442.2	Q9UK97-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FBXO9	ENST00000323557.12 link	c.1305G>C	p.Arg435Ser	missense_variant	Exon 13 of 13	1	NM_033480.3	ENSP00000326968.7	Q9UK97-2
FBXO9	ENST00000244426.10 link	c.1335G>C	p.Arg445Ser	missense_variant	Exon 12 of 12	1		ENSP00000244426.6	Q9UK97-1
FBXO9	ENST00000370939.7 link	c.1203G>C	p.Arg401Ser	missense_variant	Exon 13 of 13	1		ENSP00000359977.3	Q9UK97-3

Frequencies

GnomAD3 genomes

AF:

0.00000666

AC:

AN:

150064

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.000486

GnomAD3 exomes

AF:

0.00000409

AC:

AN:

244448

Hom.:

AF XY:

0.00

AC XY:

AN XY:

132698

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:

0.00000898

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1448126

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

720764

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:

0.00000181

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000666

AC:

AN:

150064

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73120

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.000486

Bravo

AF:

0.00000378

ExAC

AF:

0.00000828

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000602

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1335G>C (p.R445S) alteration is located in exon 12 (coding exon 12) of the FBXO9 gene. This alteration results from a G to C substitution at nucleotide position 1335, causing the arginine (R) at amino acid position 445 to be replaced by a serine (S). 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

0.22

BayesDel_addAF

Benign

-0.012

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.037

.;.;T

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.16

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Benign

0.020

MetaRNN

Benign

0.085

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.1

.;.;L

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.32

N;N;N

REVEL

Benign

0.22

Sift

Benign

0.67

T;T;T

Sift4G

Benign

0.86

T;T;T

Polyphen

0.0010, 0.0090

.;B;B

Vest4

0.22

MutPred

0.14

.;.;Gain of glycosylation at R445 (P = 0.0283);

MVP

0.40

MPC

0.46

ClinPred

0.30

GERP RS

2.7

Varity_R

0.13

gMVP

0.21

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