6-53071051-C-G

Variant names:

• chr6-53071051-C-G
• ENST00000244426.10:c.28C>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_012347.4(FBXO9):​c.28C>G​(p.Pro10Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000707 in 1,415,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: FBXO9 NM_012347.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.351

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.051736444).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXO9	NM_033480.3	c.4-6C>G		splice_region_variant, intron_variant	Intron 1 of 12	ENST00000323557.12	NP_258441.1
FBXO9	NM_012347.4	c.28C>G	p.Pro10Ala	missense_variant	Exon 1 of 12		NP_036479.1
FBXO9	NM_033481.3	c.-99-6C>G		splice_region_variant, intron_variant	Intron 1 of 12		NP_258442.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBXO9	ENST00000244426.10	c.28C>G	p.Pro10Ala	missense_variant	Exon 1 of 12	1		ENSP00000244426.6
FBXO9	ENST00000323557.12	c.4-6C>G		splice_region_variant, intron_variant	Intron 1 of 12	1	NM_033480.3	ENSP00000326968.7
FBXO9	ENST00000370939.7	c.-99-6C>G		splice_region_variant, intron_variant	Intron 1 of 12	1		ENSP00000359977.3
FBXO9	ENST00000498744.5	c.-99-6C>G		splice_region_variant, intron_variant	Intron 2 of 6	3		ENSP00000418858.1
FBXO9	ENST00000473337.6	c.-99-6C>G		splice_region_variant, intron_variant	Intron 1 of 5	4		ENSP00000420536.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.07e-7 AC: 1 AN: 1415114 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 699244

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: 9.21e-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

Dec 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.28C>G (p.P10A) alteration is located in exon 1 (coding exon 1) of the FBXO9 gene. This alteration results from a C to G substitution at nucleotide position 28, causing the proline (P) at amino acid position 10 to be replaced by an alanine (A). 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	0.063
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	7.9
DANN	Benign	0.73
DEOGEN2	Benign	0.035	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.26	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.052	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PROVEAN	Benign	0.28	N
REVEL	Benign	0.17
Sift	Benign	0.84	T
Vest4		0.12
MutPred		0.11		Gain of helix (P = 0.0496);
MVP		0.55
MPC		0.39
ClinPred		0.053	T
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.029
gMVP		0.045

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: chr6-52935849;