11-33747149-C-T

Variant names:

• chr11-33747149-C-T
• rs757065450
• NM_012175.4:c.1220G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012175.4(FBXO3):​c.1220G>A​(p.Arg407Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,486 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: FBXO3 NM_012175.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.19
• Publications: 0 publications found

Genes affected

FBXO3 (HGNC:13582): (F-box protein 3) 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. Alternative splicing of this gene generates 2 transcript variants diverging at the 3' end. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.085195124).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012175.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXO3	NM_012175.4	MANE Select	c.1220G>A	p.Arg407Lys	missense	Exon 10 of 11	NP_036307.2
	FBXO3	NM_033406.4		c.1220G>A	p.Arg407Lys	missense	Exon 10 of 10	NP_208385.1	Q9UK99-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXO3	ENST00000265651.8	TSL:1 MANE Select	c.1220G>A	p.Arg407Lys	missense	Exon 10 of 11	ENSP00000265651.3	Q9UK99-1
	FBXO3	ENST00000448981.6	TSL:1	c.1220G>A	p.Arg407Lys	missense	Exon 10 of 10	ENSP00000408836.2	Q9UK99-2
	FBXO3	ENST00000526785.5	TSL:1	c.881G>A	p.Arg294Lys	missense	Exon 9 of 10	ENSP00000435680.1	G3V1E0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000406 AC: 1 AN: 246442 AF XY: 0.00000749

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457486 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 725224

African (AFR) AF: 0.00 AC: 0 AN: 33128

American (AMR) AF: 0.00 AC: 0 AN: 42866

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25970

East Asian (EAS) AF: 0.00 AC: 0 AN: 39648

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85600

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110998

Other (OTH) AF: 0.00 AC: 0 AN: 60188

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.078
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.085	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.92	L
PhyloP100		3.2
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.060	N
REVEL	Benign	0.080
Sift	Benign	0.38	T
Sift4G	Benign	0.75	T
Polyphen		0.0010	B
Vest4		0.15
MutPred		0.40		Gain of methylation at R407 (P = 0.0039)
MVP		0.42
MPC		0.59
ClinPred		0.27	T
GERP RS		4.4
Varity_R		0.13
gMVP		0.58
Mutation Taster		=74/26	polymorphism

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: rs757065450; hg19: chr11-33768695;