11-33742003-C-G

Variant names:

• chr11-33742003-C-G
• NM_012175.4:c.1321G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012175.4(FBXO3):​c.1321G>C​(p.Asp441His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FBXO3 NM_012175.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.38

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20102525).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXO3	NM_012175.4	c.1321G>C	p.Asp441His	missense_variant	Exon 11 of 11	ENST00000265651.8	NP_036307.2
FBXO3	NM_033406.4	c.*5118G>C		3_prime_UTR_variant	Exon 10 of 10		NP_208385.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBXO3	ENST00000265651.8	c.1321G>C	p.Asp441His	missense_variant	Exon 11 of 11	1	NM_012175.4	ENSP00000265651.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1321G>C (p.D441H) alteration is located in exon 11 (coding exon 11) of the FBXO3 gene. This alteration results from a G to C substitution at nucleotide position 1321, causing the aspartic acid (D) at amino acid position 441 to be replaced by a histidine (H). 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	Benign	0.20
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	23
DANN	Uncertain	0.97
DEOGEN2	Benign	0.0096	T;T;.;.
Eigen	Benign	0.088
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.76	T;T;.;T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.20	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	.;L;.;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.34	N;N;N;N
REVEL	Benign	0.046
Sift	Benign	0.29	T;T;T;T
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		0.61	.;P;.;.
Vest4		0.32
MutPred		0.13		.;Loss of stability (P = 0.0935);.;.;
MVP		0.44
MPC		0.69
ClinPred		0.48	T
GERP RS		4.8
Varity_R		0.15
gMVP		0.40

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-33763549;