Variant 8-123504695-ATCT-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PM4_SupportingPP5_Moderate

The NM_058229.4(FBXO32):c.884_886delAGA(p.Lys295del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.000000684 in 1,461,812 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

FBXO32
NM_058229.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 6.14

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 links:

FBXO32 (HGNC:):

FBXO32 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_058229.4. Strenght limited to Supporting due to length of the change: 1aa.

PP5

Variant 8-123504695-ATCT-A is Pathogenic according to our data. Variant chr8-123504695-ATCT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1188824.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBXO32	NM_058229.4 linkuse as main transcript	c.884_886delAGA	p.Lys295del	disruptive_inframe_deletion	8/9	ENST00000517956.5	NP_478136.1	Q969P5-1A0A024R9F3
FBXO32	NM_001242463.2 linkuse as main transcript	c.605_607delAGA	p.Lys202del	disruptive_inframe_deletion	6/7		NP_001229392.1	Q969P5-2
FBXO32	NM_148177.3 linkuse as main transcript	c.449_451delAGA	p.Lys150del	disruptive_inframe_deletion	5/6		NP_680482.1	Q0VAQ6Q498Y9I6L984

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
FBXO32	ENST00000517956.5 linkuse as main transcript	c.884_886delAGA	p.Lys295del	disruptive_inframe_deletion	8/9	1	NM_058229.4	ENSP00000428205.1	Q969P5-1
FBXO32	ENST00000443022.2 linkuse as main transcript	c.605_607delAGA	p.Lys202del	disruptive_inframe_deletion	6/7	1		ENSP00000390790.2	Q969P5-2
FBXO32	ENST00000287396.2 linkuse as main transcript	n.758_760delAGA		non_coding_transcript_exon_variant	5/6	1
FBXO32	ENST00000524000.5 linkuse as main transcript	n.284_286delAGA		non_coding_transcript_exon_variant	2/3	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461812

Hom.:

AF XY:

0.00000138

AC XY:

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

OMIM: 606604

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Rajaie Cardiovascular, Medical and Research Center, Iran University of Medical Sciences

The FBXO32 gene encodes an atrogin-1 protein, an E3 ligase, which is expressed in skeletal muscles and cardiomyocytes and plays a critical role in muscle atrophy. Due to the study of Al-Hassnan et al., 2016 (PMID: 26768247), they suggested that FBXO32 is a candidate gene for autosomal recessive Dilated cardiomyopathy. Mutated FBXO32 could perturb the degradation of target proteins in the ubiquitin proteasome system (UPS), the impairment of which has been observed in cardiomyopathy. Based on ACMG classification, c.449_451del variant is VUS. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over