chr11-33755788-C-T

Variant names:

• chr11-33755788-C-T
• rs1402954
• NM_012175.4:c.661G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_012175.4(FBXO3):​c.661G>A​(p.Val221Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0797 in 1,613,120 control chromosomes in the GnomAD database, including 5,953 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.064 (460 hom., cov: 32)
  • Exomes 𝑓: 0.081 (5493 hom.)
• Consequence: FBXO3 NM_012175.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.86
• Publications: 29 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018072724).
• BP6: Variant 11-33755788-C-T is Benign according to our data. Variant chr11-33755788-C-T is described in ClinVar as Benign. ClinVar VariationId is 1278752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.096 is higher than 0.05.

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.661G>A	p.Val221Ile	missense	Exon 5 of 11	NP_036307.2
	FBXO3	NM_033406.4		c.661G>A	p.Val221Ile	missense	Exon 5 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.661G>A	p.Val221Ile	missense	Exon 5 of 11	ENSP00000265651.3	Q9UK99-1
	FBXO3	ENST00000448981.6	TSL:1	c.661G>A	p.Val221Ile	missense	Exon 5 of 10	ENSP00000408836.2	Q9UK99-2
	FBXO3	ENST00000526785.5	TSL:1	c.322G>A	p.Val108Ile	missense	Exon 4 of 10	ENSP00000435680.1	G3V1E0

Frequencies

GnomAD3 genomes AF: 0.0642 AC: 9775 AN: 152158 Hom.: 460 Cov.: 32

Gnomad AFR AF: 0.0163

Gnomad AMI AF: 0.0614

Gnomad AMR AF: 0.0737

Gnomad ASJ AF: 0.140

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.0215

Gnomad FIN AF: 0.0468

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0979

Gnomad OTH AF: 0.0716

GnomAD2 exomes AF: 0.0661 AC: 16608 AN: 251280 AF XY: 0.0668

Gnomad AFR exome AF: 0.0144

Gnomad AMR exome AF: 0.0499

Gnomad ASJ exome AF: 0.116

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0482

Gnomad NFE exome AF: 0.0991

Gnomad OTH exome AF: 0.0875

GnomAD4 exome AF: 0.0814 AC: 118853 AN: 1460844 Hom.: 5493 Cov.: 31 AF XY: 0.0805 AC XY: 58523 AN XY: 726802

African (AFR) AF: 0.0137 AC: 459 AN: 33474

American (AMR) AF: 0.0518 AC: 2318 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.120 AC: 3126 AN: 26128

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39692

South Asian (SAS) AF: 0.0225 AC: 1938 AN: 86244

European-Finnish (FIN) AF: 0.0517 AC: 2759 AN: 53404

Middle Eastern (MID) AF: 0.0763 AC: 430 AN: 5638

European-Non Finnish (NFE) AF: 0.0927 AC: 103051 AN: 1111190

Other (OTH) AF: 0.0789 AC: 4765 AN: 60362

GnomAD4 genome AF: 0.0642 AC: 9778 AN: 152276 Hom.: 460 Cov.: 32 AF XY: 0.0611 AC XY: 4546 AN XY: 74448

African (AFR) AF: 0.0162 AC: 675 AN: 41560

American (AMR) AF: 0.0736 AC: 1125 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 485 AN: 3468

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5196

South Asian (SAS) AF: 0.0216 AC: 104 AN: 4824

European-Finnish (FIN) AF: 0.0468 AC: 496 AN: 10600

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0979 AC: 6661 AN: 68018

Other (OTH) AF: 0.0709 AC: 150 AN: 2116

Alfa AF: 0.0888 Hom.: 2476

Bravo AF: 0.0645

TwinsUK AF: 0.0874 AC: 324

ALSPAC AF: 0.0807 AC: 311

ESP6500AA AF: 0.0150 AC: 66

ESP6500EA AF: 0.102 AC: 874

ExAC AF: 0.0661 AC: 8029

Asia WGS AF: 0.0170 AC: 59 AN: 3478

EpiCase AF: 0.101

EpiControl AF: 0.108

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	20
DANN	Benign	0.61
DEOGEN2	Benign	0.0080	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.0066
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N
PhyloP100		5.9
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.040	N
REVEL	Benign	0.13
Sift	Benign	0.83	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.029
MPC		0.47
ClinPred		0.024	T
GERP RS		4.9
Varity_R		0.043
gMVP		0.26
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs1402954; hg19: chr11-33777334; COSMIC: COSV55765514; COSMIC: COSV55765514;