8-123506561-C-T

Variant names:

• chr8-123506561-C-T
• rs768219000
• NM_058229.4:c.665G>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_058229.4(FBXO32):​c.665G>A​(p.Gly222Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G222A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBXO32 NM_058229.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.84

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.761

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXO32	NM_058229.4	c.665G>A	p.Gly222Asp	missense_variant	Exon 7 of 9	ENST00000517956.5	NP_478136.1
FBXO32	NM_001242463.2	c.386G>A	p.Gly129Asp	missense_variant	Exon 5 of 7		NP_001229392.1
FBXO32	NM_148177.3	c.230G>A	p.Gly77Asp	missense_variant	Exon 4 of 6		NP_680482.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBXO32	ENST00000517956.5	c.665G>A	p.Gly222Asp	missense_variant	Exon 7 of 9	1	NM_058229.4	ENSP00000428205.1
FBXO32	ENST00000443022.2	c.386G>A	p.Gly129Asp	missense_variant	Exon 5 of 7	1		ENSP00000390790.2
FBXO32	ENST00000287396.2	n.539G>A		non_coding_transcript_exon_variant	Exon 4 of 6	1
FBXO32	ENST00000524000.5	n.65G>A		non_coding_transcript_exon_variant	Exon 1 of 3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T;.
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.024	T
MetaRNN	Pathogenic	0.76	D;D
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.3	M;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.22
Sift	Benign	0.033	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.99	D;.
Vest4		0.85
MutPred		0.57		Loss of catalytic residue at G222 (P = 0.0431);.;
MVP		0.49
MPC		1.8
ClinPred		0.91	D
GERP RS		5.1
Varity_R		0.38
gMVP		0.72

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: rs768219000; hg19: chr8-124518801;