6-53095524-C-G

Variant names:

• chr6-53095524-C-G
• NM_033480.3:c.1065C>G

Variant summary

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

The NM_033480.3(FBXO9):​c.1065C>G​(p.Asp355Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000117 in 1,458,282 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: FBXO9 NM_033480.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.50

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20450616).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXO9	NM_033480.3	c.1065C>G	p.Asp355Glu	missense_variant	Exon 12 of 13	ENST00000323557.12	NP_258441.1
FBXO9	NM_012347.4	c.1095C>G	p.Asp365Glu	missense_variant	Exon 11 of 12		NP_036479.1
FBXO9	NM_033481.3	c.963C>G	p.Asp321Glu	missense_variant	Exon 12 of 13		NP_258442.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBXO9	ENST00000323557.12	c.1065C>G	p.Asp355Glu	missense_variant	Exon 12 of 13	1	NM_033480.3	ENSP00000326968.7
FBXO9	ENST00000244426.10	c.1095C>G	p.Asp365Glu	missense_variant	Exon 11 of 12	1		ENSP00000244426.6
FBXO9	ENST00000370939.7	c.963C>G	p.Asp321Glu	missense_variant	Exon 12 of 13	1		ENSP00000359977.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000117 AC: 17 AN: 1458282 Hom.: 0 Cov.: 31 AF XY: 0.00000689 AC XY: 5 AN XY: 725310

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: 0.0000153

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1095C>G (p.D365E) alteration is located in exon 11 (coding exon 11) of the FBXO9 gene. This alteration results from a C to G substitution at nucleotide position 1095, causing the aspartic acid (D) at amino acid position 365 to be replaced by a glutamic acid (E). 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	0.13
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.042	.;.;T;.
Eigen	Benign	-0.11
Eigen_PC	Benign	0.020
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.66	T;T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.20	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.47	.;.;N;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.55	N;N;N;.
REVEL	Benign	0.22
Sift	Benign	0.47	T;T;T;.
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0020, 0.0010	.;B;B;.
Vest4		0.11
MutPred		0.32		.;.;Loss of sheet (P = 0.0104);.;
MVP		0.41
MPC		0.38
ClinPred		0.22	T
GERP RS		3.3
Varity_R		0.078
gMVP		0.14

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: chr6-52960322;