rs4130296

Positions:

• chr12-116948280-A-C

Variant summary

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

The NM_153348.3(FBXW8):​c.589-1338A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.769 in 151,982 control chromosomes in the GnomAD database, including 46,341 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 0.77 (46341 hom., cov: 31)
• Consequence: FBXW8 NM_153348.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.685

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 (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.855 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBXW8	NM_153348.3	c.589-1338A>C		intron_variant		ENST00000652555.1	NP_699179.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBXW8	ENST00000652555.1	c.589-1338A>C		intron_variant			NM_153348.3	ENSP00000498999.1
FBXW8	ENST00000455858.2	c.391-1338A>C		intron_variant		1		ENSP00000389144.2
FBXW8	ENST00000309909.10	c.277-1338A>C		intron_variant		1		ENSP00000310686.6

Frequencies

GnomAD3 genomes AF: 0.769 AC: 116827 AN: 151864 Hom.: 46327 Cov.: 31

Gnomad AFR AF: 0.551

Gnomad AMI AF: 0.893

Gnomad AMR AF: 0.857

Gnomad ASJ AF: 0.789

Gnomad EAS AF: 0.754

Gnomad SAS AF: 0.844

Gnomad FIN AF: 0.860

Gnomad MID AF: 0.794

Gnomad NFE AF: 0.861

Gnomad OTH AF: 0.768

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.769 AC: 116890 AN: 151982 Hom.: 46341 Cov.: 31 AF XY: 0.772 AC XY: 57331 AN XY: 74278

Gnomad4 AFR AF: 0.551

Gnomad4 AMR AF: 0.857

Gnomad4 ASJ AF: 0.789

Gnomad4 EAS AF: 0.754

Gnomad4 SAS AF: 0.842

Gnomad4 FIN AF: 0.860

Gnomad4 NFE AF: 0.861

Gnomad4 OTH AF: 0.768

Alfa AF: 0.846 Hom.: 111180

Bravo AF: 0.758

Asia WGS AF: 0.780 AC: 2717 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.5
DANN	Benign	0.68

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: rs4130296; hg19: chr12-117386085;