Genetic Variant FBXO32:p.Gly222Asp (chr8-123506561-C-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.84

Publications

1 publications found

Variant links:

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 Gene-Disease associations (from GenCC):

dilated cardiomyopathy
Inheritance: AR Classification: LIMITED Submitted by: ClinGen, Ambry Genetics

FBXO32 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.761

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_058229.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FBXO32	NM_058229.4	MANE Select	c.665G>A	p.Gly222Asp	missense	Exon 7 of 9	NP_478136.1	Q969P5-1
FBXO32	NM_001242463.2		c.386G>A	p.Gly129Asp	missense	Exon 5 of 7	NP_001229392.1	Q969P5-2
FBXO32	NM_148177.3		c.230G>A	p.Gly77Asp	missense	Exon 4 of 6	NP_680482.1	Q0VAQ6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FBXO32	ENST00000517956.5	TSL:1 MANE Select	c.665G>A	p.Gly222Asp	missense	Exon 7 of 9	ENSP00000428205.1	Q969P5-1
FBXO32	ENST00000443022.2	TSL:1	c.386G>A	p.Gly129Asp	missense	Exon 5 of 7	ENSP00000390790.2	Q969P5-2
FBXO32	ENST00000287396.2	TSL:1	n.539G>A		non_coding_transcript_exon	Exon 4 of 6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.060

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.024

MetaRNN

Pathogenic

0.76

MetaSVM

Benign

-0.81

MutationAssessor

Uncertain

2.3

PhyloP100

7.8

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-1.3

REVEL

Benign

0.22

Sift

Benign

0.033

Sift4G

Pathogenic

0.0

Polyphen

0.99

Vest4

0.85

MutPred

0.57

Loss of catalytic residue at G222 (P = 0.0431)

MVP

0.49

MPC

1.8

ClinPred

0.91

GERP RS

5.1

Varity_R

0.38

gMVP

0.72

Mutation Taster

=28/72

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over