8-123514302-G-A

Position:

• chr8-123514302-G-A

Variant summary

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

The NM_058229.4(FBXO32):​c.404C>T​(p.Thr135Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBXO32 NM_058229.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.96

Genes affected

FBXO32 (HGNC:16731): (F-box protein 32) 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 and contains an F-box domain. This protein is highly expressed during muscle atrophy, whereas mice deficient in this gene were found to be resistant to atrophy. This protein is thus a potential drug target for the treatment of muscle atrophy. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jun 2011]

FBXO32 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBXO32	NM_058229.4	c.404C>T	p.Thr135Ile	missense_variant	5/9	ENST00000517956.5	NP_478136.1
FBXO32	NM_148177.3	c.-32C>T		5_prime_UTR_variant	2/6		NP_680482.1
FBXO32	NM_001242463.2	c.373-7728C>T		intron_variant			NP_001229392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBXO32	ENST00000517956.5	c.404C>T	p.Thr135Ile	missense_variant	5/9	1	NM_058229.4	ENSP00000428205.1
FBXO32	ENST00000443022.2	c.373-7728C>T		intron_variant		1		ENSP00000390790.2
FBXO32	ENST00000287396.2	n.278C>T		non_coding_transcript_exon_variant	2/6	1
FBXO32	ENST00000521719.5	n.579C>T		non_coding_transcript_exon_variant	5/6	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 08, 2024

The c.404C>T (p.T135I) alteration is located in exon 5 (coding exon 5) of the FBXO32 gene. This alteration results from a C to T substitution at nucleotide position 404, causing the threonine (T) at amino acid position 135 to be replaced by an isoleucine (I). 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	Pathogenic	0.89
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.9	L
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.29
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.030	D
Polyphen		0.97	D
Vest4		0.55
MutPred		0.44		Gain of helix (P = 0.062);
MVP		0.37
MPC		1.4
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.41
gMVP		0.31

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: rs1816794962; hg19: chr8-124526542;