Variant 4-174239149-C-T details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_012180.3(FBXO8):c.617G>A(p.Arg206Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000169 in 1,593,218 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

FBXO8
NM_012180.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.28

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]

FBXO8 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=0.24376419).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBXO8	NM_012180.3 linkuse as main transcript	c.617G>A	p.Arg206Lys	missense_variant	5/6	ENST00000393674.7	NP_036312.2	Q9NRD0-1A0A0S2Z5D1Q8IXA8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBXO8	ENST00000393674.7 linkuse as main transcript	c.617G>A	p.Arg206Lys	missense_variant	5/6	1	NM_012180.3	ENSP00000377280.2		Q9NRD0-1

Frequencies

GnomAD3 genomes

AF:

0.00000660

AC:

AN:

151504

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:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000125

AC:

AN:

239712

Hom.:

AF XY:

0.0000154

AC XY:

AN XY:

129972

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:

0.0000274

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000180

AC:

AN:

1441714

Hom.:

Cov.:

AF XY:

0.0000181

AC XY:

AN XY:

717244

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:

0.0000227

Gnomad4 OTH exome

AF:

0.0000169

GnomAD4 genome

AF:

0.00000660

AC:

AN:

151504

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73982

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:

0.0000148

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000508

Hom.:

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 01, 2021

The c.617G>A (p.R206K) alteration is located in exon 5 (coding exon 4) of the FBXO8 gene. This alteration results from a G to A substitution at nucleotide position 617, causing the arginine (R) at amino acid position 206 to be replaced by a lysine (K). 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

0.099

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.037

.;T;.

Eigen

Benign

-0.17

Eigen_PC

Benign

0.089

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.90

D;D;.

M_CAP

Benign

0.011

MetaRNN

Benign

0.24

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.41

.;N;.

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

0.52

.;N;N

REVEL

Benign

0.086

Sift

Benign

0.50

.;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.016

.;B;.

Vest4

0.34

MutPred

0.39

.;Gain of methylation at R206 (P = 0.0242);.;

MVP

0.42

MPC

0.61

ClinPred

0.43

GERP RS

5.4

Varity_R

0.36

gMVP

0.44

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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