rs2294088

Positions:

• chr8-123514367-G-A
• chr8-123514367-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_058229.4(FBXO32):​c.373-34C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.298 in 1,558,972 control chromosomes in the GnomAD database, including 75,535 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (10601 hom., cov: 32)
  • Exomes 𝑓: 0.29 (64934 hom.)
• Consequence: FBXO32 NM_058229.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.805

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 8-123514367-G-A is Benign according to our data. Variant chr8-123514367-G-A is described in ClinVar as [Benign]. Clinvar id is 1269899.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.637 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBXO32	NM_058229.4	c.373-34C>T		intron_variant		ENST00000517956.5	NP_478136.1
FBXO32	NM_001242463.2	c.373-7793C>T		intron_variant			NP_001229392.1
FBXO32	NM_148177.3	c.-63-34C>T		intron_variant			NP_680482.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBXO32	ENST00000517956.5	c.373-34C>T		intron_variant		1	NM_058229.4	ENSP00000428205	P1
FBXO32	ENST00000443022.2	c.373-7793C>T		intron_variant		1		ENSP00000390790
FBXO32	ENST00000287396.2	n.247-34C>T		intron_variant, non_coding_transcript_variant		1
FBXO32	ENST00000521719.5	n.548-34C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.356 AC: 54024 AN: 151900 Hom.: 10584 Cov.: 32

Gnomad AFR AF: 0.464

Gnomad AMI AF: 0.238

Gnomad AMR AF: 0.431

Gnomad ASJ AF: 0.197

Gnomad EAS AF: 0.655

Gnomad SAS AF: 0.224

Gnomad FIN AF: 0.362

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.269

Gnomad OTH AF: 0.338

GnomAD3 exomes AF: 0.353 AC: 78380 AN: 221754 Hom.: 15620 AF XY: 0.335 AC XY: 40127 AN XY: 119738

Gnomad AFR exome AF: 0.469

Gnomad AMR exome AF: 0.528

Gnomad ASJ exome AF: 0.209

Gnomad EAS exome AF: 0.675

Gnomad SAS exome AF: 0.236

Gnomad FIN exome AF: 0.349

Gnomad NFE exome AF: 0.275

Gnomad OTH exome AF: 0.317

GnomAD4 exome AF: 0.292 AC: 411162 AN: 1406954 Hom.: 64934 Cov.: 21 AF XY: 0.289 AC XY: 202454 AN XY: 700892

Gnomad4 AFR exome AF: 0.468

Gnomad4 AMR exome AF: 0.512

Gnomad4 ASJ exome AF: 0.204

Gnomad4 EAS exome AF: 0.639

Gnomad4 SAS exome AF: 0.229

Gnomad4 FIN exome AF: 0.345

Gnomad4 NFE exome AF: 0.270

Gnomad4 OTH exome AF: 0.301

GnomAD4 genome AF: 0.356 AC: 54086 AN: 152018 Hom.: 10601 Cov.: 32 AF XY: 0.360 AC XY: 26785 AN XY: 74326

Gnomad4 AFR AF: 0.464

Gnomad4 AMR AF: 0.431

Gnomad4 ASJ AF: 0.197

Gnomad4 EAS AF: 0.656

Gnomad4 SAS AF: 0.224

Gnomad4 FIN AF: 0.362

Gnomad4 NFE AF: 0.269

Gnomad4 OTH AF: 0.338

Alfa AF: 0.288 Hom.: 16136

Bravo AF: 0.370

Asia WGS AF: 0.425 AC: 1475 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 11, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	13
DANN	Benign	0.82

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: rs2294088; hg19: chr8-124526607; COSMIC: COSV54892967;