6-53073623-A-T

Variant names:

• chr6-53073623-A-T
• NM_033480.3:c.233A>T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_033480.3(FBXO9):​c.233A>T​(p.Gln78Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000695 in 1,437,832 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 Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: FBXO9 NM_033480.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.28

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 -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.027161777).
• BP6: Variant 6-53073623-A-T is Benign according to our data. Variant chr6-53073623-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 3849576.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXO9	NM_033480.3	c.233A>T	p.Gln78Leu	missense_variant	Exon 3 of 13	ENST00000323557.12	NP_258441.1
FBXO9	NM_012347.4	c.263A>T	p.Gln88Leu	missense_variant	Exon 2 of 12		NP_036479.1
FBXO9	NM_033481.3	c.131A>T	p.Gln44Leu	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.233A>T	p.Gln78Leu	missense_variant	Exon 3 of 13	1	NM_033480.3	ENSP00000326968.7
FBXO9	ENST00000244426.10	c.263A>T	p.Gln88Leu	missense_variant	Exon 2 of 12	1		ENSP00000244426.6
FBXO9	ENST00000370939.7	c.131A>T	p.Gln44Leu	missense_variant	Exon 3 of 13	1		ENSP00000359977.3
FBXO9	ENST00000498744.5	c.131A>T	p.Gln44Leu	missense_variant	Exon 4 of 7	3		ENSP00000418858.1
FBXO9	ENST00000473337.6	c.131A>T	p.Gln44Leu	missense_variant	Exon 3 of 6	4		ENSP00000420536.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.95e-7 AC: 1 AN: 1437832 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 713374

Gnomad4 AFR exome AF: 0.0000305

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jan 16, 2025

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	19
DANN	Benign	0.91
DEOGEN2	Benign	0.0014	.;T;.;.;.;T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.69	T;T;T;T;T;T
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.027	T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.4	.;.;.;.;.;N
PROVEAN	Benign	0.94	N;N;N;N;N;N
REVEL	Benign	0.039
Sift	Benign	1.0	T;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T
Polyphen		0.0	.;.;.;B;.;B
Vest4		0.12, 0.12, 0.12
MutPred		0.20		.;.;.;.;.;Gain of ubiquitination at K90 (P = 0.0577);
MVP		0.082
MPC		0.39
ClinPred		0.23	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.049
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr6-52938421;