16-87333944-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_024735.5(FBXO31):c.1339G>A(p.Val447Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000912 in 1,612,278 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000090 (0 hom.)
• Consequence: FBXO31 NM_024735.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.98

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.057759494).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBXO31	NM_024735.5	c.1339G>A	p.Val447Met	missense_variant	8/9	ENST00000311635.12
FBXO31	NM_001282683.2	c.823G>A	p.Val275Met	missense_variant	9/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBXO31	ENST00000311635.12	c.1339G>A	p.Val447Met	missense_variant	8/9	1	NM_024735.5	P1
FBXO31	ENST00000636077.2	c.1426G>A	p.Val476Met	missense_variant	9/10	5
FBXO31	ENST00000618298.6	c.823G>A	p.Val275Met	missense_variant	8/9	5
FBXO31	ENST00000565593.1	c.*45G>A		3_prime_UTR_variant, NMD_transcript_variant	2/3	5

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152224 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000184 AC: 45 AN: 244738 Hom.: 0 AF XY: 0.000112 AC XY: 15 AN XY: 133398

Gnomad AFR exome AF: 0.000130

Gnomad AMR exome AF: 0.000262

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00134

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000916

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000897 AC: 131 AN: 1459936 Hom.: 0 Cov.: 32 AF XY: 0.0000799 AC XY: 58 AN XY: 726238

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000247

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000428

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000882

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152342 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74498

Gnomad4 AFR AF: 0.0000721

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000894 Hom.: 0

Bravo AF: 0.000110

ExAC AF: 0.000149 AC: 18

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 16, 2023

The c.1339G>A (p.V447M) alteration is located in exon 8 (coding exon 8) of the FBXO31 gene. This alteration results from a G to A substitution at nucleotide position 1339, causing the valine (V) at amino acid position 447 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.13
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.26	T;T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.058	T;T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Pathogenic	3.1	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.95	N;.
REVEL	Benign	0.20
Sift	Uncertain	0.0060	D;.
Sift4G	Uncertain	0.051	T;T
Polyphen		1.0	D;.
Vest4		0.45
MVP		0.64
MPC		1.9
ClinPred		0.18	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.43
gMVP		0.78

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: rs200331468; hg19: chr16-87367550; COSMIC: COSV100291627;