11-33768945-T-A

Variant names:

• chr11-33768945-T-A
• rs1236013322
• NM_012175.4:c.264A>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_012175.4(FBXO3):​c.264A>T​(p.Arg88Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,684 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FBXO3 NM_012175.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.435

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXO3	NM_012175.4	c.264A>T	p.Arg88Ser	missense_variant	Exon 3 of 11	ENST00000265651.8	NP_036307.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBXO3	ENST00000265651.8	c.264A>T	p.Arg88Ser	missense_variant	Exon 3 of 11	1	NM_012175.4	ENSP00000265651.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251340 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135844

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461684 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727146

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 06, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.264A>T (p.R88S) alteration is located in exon 3 (coding exon 3) of the FBXO3 gene. This alteration results from a A to T substitution at nucleotide position 264, causing the arginine (R) at amino acid position 88 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T;.;T;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.71	D;D;D;D
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.9	L;.;.;L
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.9	D;N;D;D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0090	D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		0.98	D;D;.;D
Vest4		0.70
MutPred		0.53		Loss of helix (P = 0.0444);.;Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);
MVP		0.74
MPC		1.1
ClinPred		0.95	D
GERP RS		4.8
Varity_R		0.53
gMVP		0.82

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: rs1236013322; hg19: chr11-33790491;