6-53095524-C-G

Variant summary

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

The NM_033480.3(FBXO9):​c.1065C>G​(p.Asp355Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000117 in 1,458,282 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

FBXO9
NM_033480.3 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.50
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=0.20450616).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FBXO9NM_033480.3 linkc.1065C>G p.Asp355Glu missense_variant Exon 12 of 13 ENST00000323557.12 NP_258441.1 Q9UK97-2
FBXO9NM_012347.4 linkc.1095C>G p.Asp365Glu missense_variant Exon 11 of 12 NP_036479.1 Q9UK97-1
FBXO9NM_033481.3 linkc.963C>G p.Asp321Glu missense_variant Exon 12 of 13 NP_258442.2 Q9UK97-3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FBXO9ENST00000323557.12 linkc.1065C>G p.Asp355Glu missense_variant Exon 12 of 13 1 NM_033480.3 ENSP00000326968.7 Q9UK97-2
FBXO9ENST00000244426.10 linkc.1095C>G p.Asp365Glu missense_variant Exon 11 of 12 1 ENSP00000244426.6 Q9UK97-1
FBXO9ENST00000370939.7 linkc.963C>G p.Asp321Glu missense_variant Exon 12 of 13 1 ENSP00000359977.3 Q9UK97-3

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.0000117
AC:
17
AN:
1458282
Hom.:
0
Cov.:
31
AF XY:
0.00000689
AC XY:
5
AN XY:
725310
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:
0.0000153
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jan 16, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1095C>G (p.D365E) alteration is located in exon 11 (coding exon 11) of the FBXO9 gene. This alteration results from a C to G substitution at nucleotide position 1095, causing the aspartic acid (D) at amino acid position 365 to be replaced by a glutamic acid (E). 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
0.13
BayesDel_addAF
Benign
-0.15
T
BayesDel_noAF
Benign
-0.45
CADD
Benign
17
DANN
Uncertain
0.98
DEOGEN2
Benign
0.042
.;.;T;.
Eigen
Benign
-0.11
Eigen_PC
Benign
0.020
FATHMM_MKL
Uncertain
0.82
D
LIST_S2
Benign
0.66
T;T;T;T
M_CAP
Benign
0.012
T
MetaRNN
Benign
0.20
T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.47
.;.;N;.
PrimateAI
Uncertain
0.60
T
PROVEAN
Benign
-0.55
N;N;N;.
REVEL
Benign
0.22
Sift
Benign
0.47
T;T;T;.
Sift4G
Benign
1.0
T;T;T;T
Polyphen
0.0020, 0.0010
.;B;B;.
Vest4
0.11
MutPred
0.32
.;.;Loss of sheet (P = 0.0104);.;
MVP
0.41
MPC
0.38
ClinPred
0.22
T
GERP RS
3.3
Varity_R
0.078
gMVP
0.14

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-52960322; API