chr8-123506455-G-A

Position:

• chr8-123506455-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_058229.4(FBXO32):​c.771C>T​(p.His257His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00329 in 1,614,096 control chromosomes in the GnomAD database, including 161 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (93 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (68 hom.)
• Consequence: FBXO32 NM_058229.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.52

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 8-123506455-G-A is Benign according to our data. Variant chr8-123506455-G-A is described in ClinVar as [Benign]. Clinvar id is 785262.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.52 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0584 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBXO32	NM_058229.4	c.771C>T	p.His257His	synonymous_variant	7/9	ENST00000517956.5	NP_478136.1
FBXO32	NM_001242463.2	c.492C>T	p.His164His	synonymous_variant	5/7		NP_001229392.1
FBXO32	NM_148177.3	c.336C>T	p.His112His	synonymous_variant	4/6		NP_680482.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBXO32	ENST00000517956.5	c.771C>T	p.His257His	synonymous_variant	7/9	1	NM_058229.4	ENSP00000428205.1
FBXO32	ENST00000443022.2	c.492C>T	p.His164His	synonymous_variant	5/7	1		ENSP00000390790.2
FBXO32	ENST00000287396.2	n.645C>T		non_coding_transcript_exon_variant	4/6	1
FBXO32	ENST00000524000.5	n.171C>T		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes AF: 0.0173 AC: 2636 AN: 152102 Hom.: 93 Cov.: 32

Gnomad AFR AF: 0.0604

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00563

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.0149

GnomAD3 exomes AF: 0.00457 AC: 1147 AN: 250786 Hom.: 37 AF XY: 0.00349 AC XY: 474 AN XY: 135746

Gnomad AFR exome AF: 0.0620

Gnomad AMR exome AF: 0.00228

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00106

Gnomad NFE exome AF: 0.000212

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00183 AC: 2674 AN: 1461876 Hom.: 68 Cov.: 31 AF XY: 0.00154 AC XY: 1118 AN XY: 727236

Gnomad4 AFR exome AF: 0.0624

Gnomad4 AMR exome AF: 0.00286

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.000730

Gnomad4 NFE exome AF: 0.000162

Gnomad4 OTH exome AF: 0.00364

GnomAD4 genome AF: 0.0173 AC: 2641 AN: 152220 Hom.: 93 Cov.: 32 AF XY: 0.0166 AC XY: 1236 AN XY: 74410

Gnomad4 AFR AF: 0.0604

Gnomad4 AMR AF: 0.00562

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.00566 Hom.: 15

Bravo AF: 0.0196

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000178

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	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.7
DANN	Benign	0.74

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: rs34225633; hg19: chr8-124518695; COSMIC: COSV105153667;