rs4076700

Positions:

• chr12-116945515-G-A
• chr12-116945515-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_153348.3(FBXW8):​c.575G>A​(p.Arg192Gln) variant causes a missense change. The variant allele was found at a frequency of 0.816 in 1,613,530 control chromosomes in the GnomAD database, including 548,051 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.69 (40554 hom., cov: 33)
  • Exomes 𝑓: 0.83 (507497 hom.)
• Consequence: FBXW8 NM_153348.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.69

Genes affected

FBXW8 (HGNC:13597): (F-box and WD repeat domain containing 8) This gene encodes a member of the F-box protein family, members of which are characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into three 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 contains a WD-40 domain, in addition to an F-box motif, so it belongs to the Fbw class. Alternatively spliced transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

FBXW8 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.0060674E-6).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.842 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBXW8	NM_153348.3	c.575G>A	p.Arg192Gln	missense_variant	3/11	ENST00000652555.1	NP_699179.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBXW8	ENST00000652555.1	c.575G>A	p.Arg192Gln	missense_variant	3/11		NM_153348.3	ENSP00000498999.1
FBXW8	ENST00000455858.2	c.377G>A	p.Arg126Gln	missense_variant	3/11	1		ENSP00000389144.2
FBXW8	ENST00000309909.10	c.263G>A	p.Arg88Gln	missense_variant	3/11	1		ENSP00000310686.6

Frequencies

GnomAD3 genomes AF: 0.691 AC: 105087 AN: 152092 Hom.: 40551 Cov.: 33

Gnomad AFR AF: 0.312

Gnomad AMI AF: 0.884

Gnomad AMR AF: 0.818

Gnomad ASJ AF: 0.777

Gnomad EAS AF: 0.749

Gnomad SAS AF: 0.782

Gnomad FIN AF: 0.860

Gnomad MID AF: 0.769

Gnomad NFE AF: 0.848

Gnomad OTH AF: 0.712

GnomAD3 exomes AF: 0.799 AC: 200184 AN: 250648 Hom.: 82468 AF XY: 0.805 AC XY: 109016 AN XY: 135438

Gnomad AFR exome AF: 0.298

Gnomad AMR exome AF: 0.877

Gnomad ASJ exome AF: 0.787

Gnomad EAS exome AF: 0.742

Gnomad SAS exome AF: 0.788

Gnomad FIN exome AF: 0.855

Gnomad NFE exome AF: 0.848

Gnomad OTH exome AF: 0.816

GnomAD4 exome AF: 0.829 AC: 1210725 AN: 1461318 Hom.: 507497 Cov.: 46 AF XY: 0.828 AC XY: 602259 AN XY: 726956

Gnomad4 AFR exome AF: 0.293

Gnomad4 AMR exome AF: 0.869

Gnomad4 ASJ exome AF: 0.794

Gnomad4 EAS exome AF: 0.744

Gnomad4 SAS exome AF: 0.789

Gnomad4 FIN exome AF: 0.854

Gnomad4 NFE exome AF: 0.850

Gnomad4 OTH exome AF: 0.801

GnomAD4 genome AF: 0.691 AC: 105119 AN: 152212 Hom.: 40554 Cov.: 33 AF XY: 0.695 AC XY: 51729 AN XY: 74432

Gnomad4 AFR AF: 0.311

Gnomad4 AMR AF: 0.819

Gnomad4 ASJ AF: 0.777

Gnomad4 EAS AF: 0.749

Gnomad4 SAS AF: 0.781

Gnomad4 FIN AF: 0.860

Gnomad4 NFE AF: 0.848

Gnomad4 OTH AF: 0.713

Alfa AF: 0.814 Hom.: 125481

Bravo AF: 0.671

TwinsUK AF: 0.854 AC: 3166

ALSPAC AF: 0.851 AC: 3278

ESP6500AA AF: 0.313 AC: 1381

ESP6500EA AF: 0.848 AC: 7289

ExAC AF: 0.788 AC: 95688

Asia WGS AF: 0.730 AC: 2540 AN: 3478

EpiCase AF: 0.844

EpiControl AF: 0.845

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.31	T;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.75	T;T
MetaRNN	Benign	0.0000010	T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.14
Sift	Benign	0.069	T;T
Sift4G	Uncertain	0.015	D;D
Polyphen		0.97	D;D
Vest4		0.19
MPC		0.19
ClinPred		0.015	T
GERP RS		5.2
Varity_R		0.072

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

Other links and lift over

dbSNP: rs4076700; hg19: chr12-117383320; COSMIC: COSV59302512; COSMIC: COSV59302512;