chr6-152974970-C-T

Variant summary

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

The NM_012177.5(FBXO5):​c.755G>A​(p.Arg252Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,014 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: not found (cov: 32)
Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

FBXO5
NM_012177.5 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0700
Variant links:
Genes affected
FBXO5 (HGNC:13584): (F-box protein 5) 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. This protein is similar to xenopus early mitotic inhibitor-1 (Emi1), which is a mitotic regulator that interacts with Cdc20 and inhibits the anaphase promoting complex. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Dec 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=0.09278792).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FBXO5NM_012177.5 linkc.755G>A p.Arg252Gln missense_variant Exon 2 of 5 ENST00000229758.8 NP_036309.1 Q9UKT4-1
FBXO5NM_001142522.3 linkc.617G>A p.Arg206Gln missense_variant Exon 2 of 5 NP_001135994.1 Q9UKT4-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FBXO5ENST00000229758.8 linkc.755G>A p.Arg252Gln missense_variant Exon 2 of 5 1 NM_012177.5 ENSP00000229758.3 Q9UKT4-1
FBXO5ENST00000367241.3 linkc.617G>A p.Arg206Gln missense_variant Exon 2 of 5 1 ENSP00000356210.3 Q9UKT4-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000120
AC:
3
AN:
250426
Hom.:
0
AF XY:
0.0000222
AC XY:
3
AN XY:
135346
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:
0.0000658
Gnomad FIN exome
AF:
0.0000464
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000684
AC:
10
AN:
1461014
Hom.:
0
Cov.:
31
AF XY:
0.0000110
AC XY:
8
AN XY:
726752
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000756
Gnomad4 SAS exome
AF:
0.0000581
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Oct 24, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.755G>A (p.R252Q) alteration is located in exon 2 (coding exon 2) of the FBXO5 gene. This alteration results from a G to A substitution at nucleotide position 755, causing the arginine (R) at amino acid position 252 to be replaced by a glutamine (Q). 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
-0.40
T
BayesDel_noAF
Benign
-0.63
CADD
Benign
14
DANN
Benign
0.84
DEOGEN2
Benign
0.060
T;.
Eigen
Benign
-1.0
Eigen_PC
Benign
-0.94
FATHMM_MKL
Benign
0.37
N
LIST_S2
Benign
0.60
T;T
M_CAP
Benign
0.011
T
MetaRNN
Benign
0.093
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.3
L;.
PrimateAI
Benign
0.23
T
PROVEAN
Benign
-0.010
N;N
REVEL
Benign
0.019
Sift
Benign
0.28
T;T
Sift4G
Benign
0.42
T;T
Polyphen
0.27
B;.
Vest4
0.080
MutPred
0.34
Loss of MoRF binding (P = 0.0635);.;
MVP
0.36
MPC
0.40
ClinPred
0.049
T
GERP RS
-0.72
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.028
gMVP
0.097

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: rs779399211; hg19: chr6-153296105; COSMIC: COSV57671218; COSMIC: COSV57671218; API