4-174237491-C-T

Variant summary

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

The NM_012180.3(FBXO8):​c.881G>A​(p.Arg294His) variant causes a missense change. The variant allele was found at a frequency of 0.0000112 in 1,613,646 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. R294R) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

FBXO8
NM_012180.3 missense

Scores

2
5
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.08
Variant links:
Genes affected
FBXO8 (HGNC:13587): (F-box protein 8) 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. It contains a C-terminal amino acid sequence that bears a significant similarity with a portion of yeast Sec7p, a critical regulator of vesicular protein transport. This human protein may interact with ADP-ribosylation factor(s)(ARFs) and exhibit ARF-GEF (guanine nucleotide exchange factor) activity. [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=0.17968494).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FBXO8NM_012180.3 linkc.881G>A p.Arg294His missense_variant Exon 6 of 6 ENST00000393674.7 NP_036312.2 Q9NRD0-1A0A0S2Z5D1Q8IXA8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FBXO8ENST00000393674.7 linkc.881G>A p.Arg294His missense_variant Exon 6 of 6 1 NM_012180.3 ENSP00000377280.2 Q9NRD0-1

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152046
Hom.:
0
Cov.:
32
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:
0.000577
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000478
AC:
12
AN:
250914
Hom.:
0
AF XY:
0.0000516
AC XY:
7
AN XY:
135622
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000489
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000177
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000958
AC:
14
AN:
1461600
Hom.:
0
Cov.:
31
AF XY:
0.00000963
AC XY:
7
AN XY:
727102
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000151
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000630
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152046
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74258
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000577
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000340
ExAC
AF:
0.0000576
AC:
7
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jul 26, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.881G>A (p.R294H) alteration is located in exon 6 (coding exon 5) of the FBXO8 gene. This alteration results from a G to A substitution at nucleotide position 881, causing the arginine (R) at amino acid position 294 to be replaced by a histidine (H). 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
Uncertain
0.51
BayesDel_addAF
Benign
-0.15
T
BayesDel_noAF
Benign
-0.12
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.088
.;T;.
Eigen
Uncertain
0.28
Eigen_PC
Uncertain
0.42
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.94
D;D;.
M_CAP
Benign
0.021
T
MetaRNN
Benign
0.18
T;T;T
MetaSVM
Benign
-0.91
T
MutationAssessor
Benign
1.2
.;L;.
PrimateAI
Pathogenic
0.90
D
PROVEAN
Benign
-1.1
.;N;N
REVEL
Benign
0.24
Sift
Benign
0.14
.;T;T
Sift4G
Benign
0.093
T;T;T
Polyphen
0.64
.;P;.
Vest4
0.57
MutPred
0.46
.;Gain of glycosylation at T292 (P = 0.0136);.;
MVP
0.75
MPC
1.1
ClinPred
0.16
T
GERP RS
5.5
Varity_R
0.16
gMVP
0.57

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: rs747265345; hg19: chr4-175158642; COSMIC: COSV67032361; COSMIC: COSV67032361; API