chr12-116945515-G-A

Variant names:

• chr12-116945515-G-A
• rs4076700
• NM_153348.3:c.575G>A

Variant summary

Our verdict is Benign. The variant received -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.

• 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
• Publications: 45 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153348.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXW8	NM_153348.3	MANE Select	c.575G>A	p.Arg192Gln	missense	Exon 3 of 11	NP_699179.2
	FBXW8	NM_012174.2		c.377G>A	p.Arg126Gln	missense	Exon 3 of 11	NP_036306.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXW8	ENST00000652555.1	MANE Select	c.575G>A	p.Arg192Gln	missense	Exon 3 of 11	ENSP00000498999.1
	FBXW8	ENST00000455858.2	TSL:1	c.377G>A	p.Arg126Gln	missense	Exon 3 of 11	ENSP00000389144.2
	FBXW8	ENST00000309909.11	TSL:1	c.263G>A	p.Arg88Gln	missense	Exon 3 of 11	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

GnomAD2 exomes AF: 0.799 AC: 200184 AN: 250648 AF XY: 0.805

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 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

African (AFR) AF: 0.293 AC: 9794 AN: 33470

American (AMR) AF: 0.869 AC: 38822 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.794 AC: 20739 AN: 26118

East Asian (EAS) AF: 0.744 AC: 29517 AN: 39686

South Asian (SAS) AF: 0.789 AC: 67996 AN: 86200

European-Finnish (FIN) AF: 0.854 AC: 45599 AN: 53400

Middle Eastern (MID) AF: 0.780 AC: 4443 AN: 5694

European-Non Finnish (NFE) AF: 0.850 AC: 945480 AN: 1111710

Other (OTH) AF: 0.801 AC: 48335 AN: 60356

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

African (AFR) AF: 0.311 AC: 12916 AN: 41492

American (AMR) AF: 0.819 AC: 12528 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.777 AC: 2699 AN: 3472

East Asian (EAS) AF: 0.749 AC: 3882 AN: 5180

South Asian (SAS) AF: 0.781 AC: 3771 AN: 4830

European-Finnish (FIN) AF: 0.860 AC: 9119 AN: 10606

Middle Eastern (MID) AF: 0.779 AC: 229 AN: 294

European-Non Finnish (NFE) AF: 0.848 AC: 57666 AN: 68020

Other (OTH) AF: 0.713 AC: 1503 AN: 2108

Alfa AF: 0.795 Hom.: 164548

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 v4.9

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
MetaRNN	Benign	0.0000010	T
MetaSVM	Benign	-1.1	T
PhyloP100		4.7
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.14
Sift	Benign	0.069	T
Sift4G	Uncertain	0.015	D
Polyphen		0.97	D
Vest4		0.19
MPC		0.19
ClinPred		0.015	T
GERP RS		5.2
Varity_R		0.072
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

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