6-53092788-G-A

Variant names:

• chr6-53092788-G-A
• NM_033480.3:c.827G>A

Variant summary

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

The NM_033480.3(FBXO9):​c.827G>A​(p.Gly276Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBXO9 NM_033480.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.52

Genes affected

FBXO9 (HGNC:13588): (F-box protein 9) 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 at least 3 transcript variants diverging at the 5' terminus. [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
FBXO9	NM_033480.3	c.827G>A	p.Gly276Asp	missense_variant	Exon 9 of 13	ENST00000323557.12	NP_258441.1
FBXO9	NM_012347.4	c.857G>A	p.Gly286Asp	missense_variant	Exon 8 of 12		NP_036479.1
FBXO9	NM_033481.3	c.725G>A	p.Gly242Asp	missense_variant	Exon 9 of 13		NP_258442.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBXO9	ENST00000323557.12	c.827G>A	p.Gly276Asp	missense_variant	Exon 9 of 13	1	NM_033480.3	ENSP00000326968.7
FBXO9	ENST00000244426.10	c.857G>A	p.Gly286Asp	missense_variant	Exon 8 of 12	1		ENSP00000244426.6
FBXO9	ENST00000370939.7	c.725G>A	p.Gly242Asp	missense_variant	Exon 9 of 13	1		ENSP00000359977.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.857G>A (p.G286D) alteration is located in exon 8 (coding exon 8) of the FBXO9 gene. This alteration results from a G to A substitution at nucleotide position 857, causing the glycine (G) at amino acid position 286 to be replaced by an aspartic acid (D). 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	0.91
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.051	.;.;T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Benign	0.058	D
MetaRNN	Uncertain	0.71	D;D;D
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.6	.;.;M
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-1.4	N;N;N
REVEL	Uncertain	0.45
Sift	Benign	0.12	T;T;T
Sift4G	Benign	0.63	T;T;T
Polyphen		0.95, 0.15	.;P;B
Vest4		0.89
MutPred		0.39		.;.;Gain of sheet (P = 0.0266);
MVP		0.79
MPC		1.4
ClinPred		0.89	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.35
gMVP		0.77

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: chr6-52957586;