16-87333876-G-A

Position:

• chr16-87333876-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_024735.5(FBXO31):​c.1397+10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00133 in 1,588,300 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (5 hom., cov: 34)
  • Exomes 𝑓: 0.0013 (28 hom.)
• Consequence: FBXO31 NM_024735.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.64

Genes affected

FBXO31 (HGNC:16510): (F-box protein 31) This gene is a member of the F-box family. Members are classified into three classes according to the substrate interaction domain, FBW for WD40 repeats, FBL for leucing-rich repeats, and FBXO for other domains. This protein, classified into the last category because of the lack of a recognizable substrate binding domain, has been proposed to be a component of the SCF ubiquitination complex. It is thought to bind and recruit substrate for ubiquitination and degradation. This protein may have a role in regulating the cell cycle as well as dendrite growth and neuronal migration. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 16-87333876-G-A is Benign according to our data. Variant chr16-87333876-G-A is described in ClinVar as [Benign]. Clinvar id is 708552.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00169 (257/152322) while in subpopulation EAS AF= 0.0377 (195/5172). AF 95% confidence interval is 0.0334. There are 5 homozygotes in gnomad4. There are 151 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBXO31	NM_024735.5	c.1397+10C>T		intron_variant		ENST00000311635.12
FBXO31	NM_001282683.2	c.881+10C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBXO31	ENST00000311635.12	c.1397+10C>T		intron_variant		1	NM_024735.5	P1
FBXO31	ENST00000618298.6	c.881+10C>T		intron_variant		5
FBXO31	ENST00000636077.2	c.1484+10C>T		intron_variant		5
FBXO31	ENST00000565593.1	c.*103+10C>T		intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00171 AC: 260 AN: 152204 Hom.: 5 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0382

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.00310

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00332 AC: 764 AN: 230172 Hom.: 16 AF XY: 0.00302 AC XY: 376 AN XY: 124668

Gnomad AFR exome AF: 0.0000655

Gnomad AMR exome AF: 0.0000609

Gnomad ASJ exome AF: 0.000122

Gnomad EAS exome AF: 0.0378

Gnomad SAS exome AF: 0.000987

Gnomad FIN exome AF: 0.00147

Gnomad NFE exome AF: 0.000224

Gnomad OTH exome AF: 0.00145

GnomAD4 exome AF: 0.00129 AC: 1851 AN: 1435978 Hom.: 28 Cov.: 32 AF XY: 0.00126 AC XY: 896 AN XY: 711246

Gnomad4 AFR exome AF: 0.0000606

Gnomad4 AMR exome AF: 0.0000700

Gnomad4 ASJ exome AF: 0.0000411

Gnomad4 EAS exome AF: 0.0376

Gnomad4 SAS exome AF: 0.00133

Gnomad4 FIN exome AF: 0.000965

Gnomad4 NFE exome AF: 0.0000948

Gnomad4 OTH exome AF: 0.00152

GnomAD4 genome AF: 0.00169 AC: 257 AN: 152322 Hom.: 5 Cov.: 34 AF XY: 0.00203 AC XY: 151 AN XY: 74486

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0377

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00310

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000604 Hom.: 0

Bravo AF: 0.00186

Asia WGS AF: 0.0130 AC: 46 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

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	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

FBXO31-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 15, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.35
DANN	Benign	0.64
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs75105531; hg19: chr16-87367482; COSMIC: COSV61152238;