6-53071066-G-A

Variant names:

• chr6-53071066-G-A
• rs1768898653
• NM_033480.3:c.13G>A

Variant summary

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

The NM_033480.3(FBXO9):​c.13G>A​(p.Glu5Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000704 in 1,420,734 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: FBXO9 NM_033480.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.06

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=0.22998849).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXO9	NM_033480.3	c.13G>A	p.Glu5Lys	missense_variant	Exon 2 of 13	ENST00000323557.12	NP_258441.1
FBXO9	NM_012347.4	c.43G>A	p.Glu15Lys	missense_variant	Exon 1 of 12		NP_036479.1
FBXO9	NM_033481.3	c.-90G>A		5_prime_UTR_variant	Exon 2 of 13		NP_258442.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBXO9	ENST00000323557.12	c.13G>A	p.Glu5Lys	missense_variant	Exon 2 of 13	1	NM_033480.3	ENSP00000326968.7
FBXO9	ENST00000244426.10	c.43G>A	p.Glu15Lys	missense_variant	Exon 1 of 12	1		ENSP00000244426.6
FBXO9	ENST00000370939	c.-90G>A		5_prime_UTR_variant	Exon 2 of 13	1		ENSP00000359977.3
FBXO9	ENST00000498744	c.-90G>A		5_prime_UTR_variant	Exon 3 of 7	3		ENSP00000418858.1
FBXO9	ENST00000473337.6	c.-90G>A		5_prime_UTR_variant	Exon 2 of 6	4		ENSP00000420536.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.04e-7 AC: 1 AN: 1420734 Hom.: 0 Cov.: 30 AF XY: 0.00000142 AC XY: 1 AN XY: 702472

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: 9.18e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.43G>A (p.E15K) alteration is located in exon 1 (coding exon 1) of the FBXO9 gene. This alteration results from a G to A substitution at nucleotide position 43, causing the glutamic acid (E) at amino acid position 15 to be replaced by a lysine (K). 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	0.17
BayesDel_addAF	Uncertain	0.070	D
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.040	.;T
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.23	T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.2	.;L
PROVEAN	Benign	-0.70	N;N
REVEL	Uncertain	0.35
Sift	Benign	0.032	D;D
Sift4G	Benign	0.61	T;T
Polyphen		0.37	B;.
Vest4		0.49
MutPred		0.17		.;Gain of ubiquitination at E15 (P = 0.0066);
MVP		0.65
MPC		0.51
ClinPred		0.83	D
GERP RS		5.9
Varity_R		0.15
gMVP		0.19

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: rs1768898653; hg19: chr6-52935864;