6-53073596-C-T

Variant names:

• chr6-53073596-C-T
• rs771154563
• NM_033480.3:c.206C>T

Variant summary

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

The NM_033480.3(FBXO9):​c.206C>T​(p.Ser69Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000255 in 1,607,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: FBXO9 NM_033480.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.52

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 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=0.026408643).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXO9	NM_033480.3	c.206C>T	p.Ser69Leu	missense_variant	Exon 3 of 13	ENST00000323557.12	NP_258441.1
FBXO9	NM_012347.4	c.236C>T	p.Ser79Leu	missense_variant	Exon 2 of 12		NP_036479.1
FBXO9	NM_033481.3	c.104C>T	p.Ser35Leu	missense_variant	Exon 3 of 13		NP_258442.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBXO9	ENST00000323557.12	c.206C>T	p.Ser69Leu	missense_variant	Exon 3 of 13	1	NM_033480.3	ENSP00000326968.7
FBXO9	ENST00000244426.10	c.236C>T	p.Ser79Leu	missense_variant	Exon 2 of 12	1		ENSP00000244426.6
FBXO9	ENST00000370939.7	c.104C>T	p.Ser35Leu	missense_variant	Exon 3 of 13	1		ENSP00000359977.3
FBXO9	ENST00000498744.5	c.104C>T	p.Ser35Leu	missense_variant	Exon 4 of 7	3		ENSP00000418858.1
FBXO9	ENST00000473337.6	c.104C>T	p.Ser35Leu	missense_variant	Exon 3 of 6	4		ENSP00000420536.1

Frequencies

GnomAD3 genomes AF: 0.0000527 AC: 8 AN: 151790 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000955

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000930 AC: 22 AN: 236668 Hom.: 0 AF XY: 0.000101 AC XY: 13 AN XY: 128128

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000605

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000936

Gnomad SAS exome AF: 0.0000685

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000941

Gnomad OTH exome AF: 0.000172

GnomAD4 exome AF: 0.0000220 AC: 32 AN: 1455170 Hom.: 0 Cov.: 31 AF XY: 0.0000277 AC XY: 20 AN XY: 723224

Gnomad4 AFR exome AF: 0.0000599

Gnomad4 AMR exome AF: 0.0000458

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000303

Gnomad4 SAS exome AF: 0.0000235

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000992

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 151902 Hom.: 0 Cov.: 32 AF XY: 0.0000674 AC XY: 5 AN XY: 74202

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.0000955

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.0000994 AC: 12

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.236C>T (p.S79L) alteration is located in exon 2 (coding exon 2) of the FBXO9 gene. This alteration results from a C to T substitution at nucleotide position 236, causing the serine (S) at amino acid position 79 to be replaced by a leucine (L). 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	0.068
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.010	.;T;.;.;.;T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.72	T;T;T;T;T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.026	T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.4	.;.;.;.;.;L
PROVEAN	Benign	-2.0	N;N;N;N;N;N
REVEL	Benign	0.15
Sift	Uncertain	0.0060	D;T;T;T;T;T
Sift4G	Uncertain	0.038	D;T;T;T;T;T
Polyphen		0.065, 0.063	.;.;.;B;.;B
Vest4		0.10, 0.098
MutPred		0.26		.;.;.;.;.;Gain of helix (P = 0.0225);
MVP		0.43
MPC		0.36
ClinPred		0.038	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.055
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs771154563; hg19: chr6-52938394; COSMIC: COSV55056396; COSMIC: COSV55056396;