4-174237602-G-A

Variant names:

• chr4-174237602-G-A
• rs115274413
• NM_012180.3:c.773-3C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 2 publications found

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

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 21 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012180.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXO8	NM_012180.3	MANE Select	c.773-3C>T		splice_region intron	N/A	NP_036312.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXO8	ENST00000393674.7	TSL:1 MANE Select	c.773-3C>T		splice_region intron	N/A	ENSP00000377280.2	Q9NRD0-1
	FBXO8	ENST00000503293.5	TSL:1	c.650-3C>T		splice_region intron	N/A	ENSP00000422905.1	Q9NRD0-2
	FBXO8	ENST00000615392.4	TSL:1	c.650-3C>T		splice_region intron	N/A	ENSP00000484517.1	Q9NRD0-2

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

GnomAD2 exomes AF: 0.00224 AC: 530 AN: 236770 AF XY: 0.00164

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 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

African (AFR) AF: 0.0339 AC: 1094 AN: 32246

American (AMR) AF: 0.00131 AC: 54 AN: 41078

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39024

South Asian (SAS) AF: 0.0000363 AC: 3 AN: 82744

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52802

Middle Eastern (MID) AF: 0.00124 AC: 7 AN: 5644

European-Non Finnish (NFE) AF: 0.0000330 AC: 36 AN: 1091366

Other (OTH) AF: 0.00134 AC: 79 AN: 58756

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

African (AFR) AF: 0.0299 AC: 1241 AN: 41504

American (AMR) AF: 0.00210 AC: 32 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000736 AC: 5 AN: 67932

Other (OTH) AF: 0.00521 AC: 11 AN: 2110

Alfa AF: 0.00389 Hom.: 9

Bravo AF: 0.00966

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	8.6
DANN	Benign	0.48
PhyloP100		3.8
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs115274413; hg19: chr4-175158753;