4-174237602-G-A

Position:

• chr4-174237602-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_012180.3(FBXO8):​c.773-3C>T variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00162 in 1,580,840 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0085 (21 hom., cov: 32)
  • Exomes 𝑓: 0.00089 (23 hom.)
• Consequence: FBXO8 NM_012180.3 splice_region, intron
• Scores: Splicing: ADA: 0.001288
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.83

Genes affected

FBXO8 (HGNC:13587): (F-box protein 8) 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. It contains a C-terminal amino acid sequence that bears a significant similarity with a portion of yeast Sec7p, a critical regulator of vesicular protein transport. This human protein may interact with ADP-ribosylation factor(s)(ARFs) and exhibit ARF-GEF (guanine nucleotide exchange factor) activity. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 4-174237602-G-A is Benign according to our data. Variant chr4-174237602-G-A is described in ClinVar as [Benign]. Clinvar id is 791991.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00849 (1291/152078) while in subpopulation AFR AF= 0.0299 (1241/41504). AF 95% confidence interval is 0.0285. There are 21 homozygotes in gnomad4. There are 618 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 21 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBXO8	NM_012180.3	c.773-3C>T		splice_region_variant, intron_variant		ENST00000393674.7	NP_036312.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBXO8	ENST00000393674.7	c.773-3C>T		splice_region_variant, intron_variant		1	NM_012180.3	ENSP00000377280.2
FBXO8	ENST00000503293.5	c.650-3C>T		splice_region_variant, intron_variant		1		ENSP00000422905.1
FBXO8	ENST00000615392.4	c.650-3C>T		splice_region_variant, intron_variant		1		ENSP00000484517.1
FBXO8	ENST00000515664.5	n.*382-3C>T		splice_region_variant, intron_variant		5		ENSP00000427313.1

Frequencies

GnomAD3 genomes AF: 0.00846 AC: 1285 AN: 151960 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.0298

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00210

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000736

Gnomad OTH AF: 0.00527

GnomAD3 exomes AF: 0.00224 AC: 530 AN: 236770 Hom.: 7 AF XY: 0.00164 AC XY: 210 AN XY: 128142

Gnomad AFR exome AF: 0.0310

Gnomad AMR exome AF: 0.00109

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000371

Gnomad OTH exome AF: 0.000706

GnomAD4 exome AF: 0.000891 AC: 1273 AN: 1428762 Hom.: 23 Cov.: 30 AF XY: 0.000786 AC XY: 555 AN XY: 706536

Gnomad4 AFR exome AF: 0.0339

Gnomad4 AMR exome AF: 0.00131

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000363

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000330

Gnomad4 OTH exome AF: 0.00134

GnomAD4 genome AF: 0.00849 AC: 1291 AN: 152078 Hom.: 21 Cov.: 32 AF XY: 0.00831 AC XY: 618 AN XY: 74328

Gnomad4 AFR AF: 0.0299

Gnomad4 AMR AF: 0.00210

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000736

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00445 Hom.: 9

Bravo AF: 0.00966

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	8.6
DANN	Benign	0.48

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0013
dbscSNV1_RF	Benign	0.21
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: rs115274413; hg19: chr4-175158753;