6-53073559-C-A

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.169C>A(p.Pro57Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,460,480 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 (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

FBXO9
NM_033480.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.143

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=0.076636046).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXO9	NM_033480.3 link	c.169C>A	p.Pro57Thr	missense_variant	Exon 3 of 13	ENST00000323557.12	NP_258441.1	Q9UK97-2
FBXO9	NM_012347.4 link	c.199C>A	p.Pro67Thr	missense_variant	Exon 2 of 12		NP_036479.1	Q9UK97-1
FBXO9	NM_033481.3 link	c.67C>A	p.Pro23Thr	missense_variant	Exon 3 of 13		NP_258442.2	Q9UK97-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FBXO9	ENST00000323557.12 link	c.169C>A	p.Pro57Thr	missense_variant	Exon 3 of 13	1	NM_033480.3	ENSP00000326968.7	Q9UK97-2
FBXO9	ENST00000244426.10 link	c.199C>A	p.Pro67Thr	missense_variant	Exon 2 of 12	1		ENSP00000244426.6	Q9UK97-1
FBXO9	ENST00000370939.7 link	c.67C>A	p.Pro23Thr	missense_variant	Exon 3 of 13	1		ENSP00000359977.3	Q9UK97-3
FBXO9	ENST00000498744.5 link	c.67C>A	p.Pro23Thr	missense_variant	Exon 4 of 7	3		ENSP00000418858.1	C9IY65
FBXO9	ENST00000473337.6 link	c.67C>A	p.Pro23Thr	missense_variant	Exon 3 of 6	4		ENSP00000420536.1	C9JDZ9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000203

AC:

AN:

246742

Hom.:

AF XY:

0.0000224

AC XY:

AN XY:

133748

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:

0.0000448

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000548

AC:

AN:

1460480

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

726332

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00000540

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.199C>A (p.P67T) alteration is located in exon 2 (coding exon 2) of the FBXO9 gene. This alteration results from a C to A substitution at nucleotide position 199, causing the proline (P) at amino acid position 67 to be replaced by a threonine (T). 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

0.069

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Benign

0.85

DEOGEN2

Benign

0.0081

.;T;.;.;.;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.68

T;T;T;T;T;T

M_CAP

Benign

0.028

MetaRNN

Benign

0.077

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

.;.;.;.;.;L

PROVEAN

Pathogenic

-5.2

D;N;N;N;N;N

REVEL

Benign

0.088

Sift

Uncertain

0.010

D;D;D;T;D;D

Sift4G

Benign

0.088

T;T;T;T;T;T

Polyphen

0.0020, 0.0010

.;.;.;B;.;B

Vest4

0.12, 0.075, 0.078

MutPred

0.25

.;.;.;.;.;Loss of catalytic residue at P67 (P = 0.0058);

MVP

0.26

MPC

0.45

ClinPred

0.089

GERP RS

-0.50

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.066

gMVP

0.11

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