rs141286570

chr22-32498414-G-Achr22-32498414-G-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_012179.4(FBXO7):c.1453G>A(p.Val485Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00072 in 1,614,182 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V485L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00052 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00074 (2 hom.)
• Consequence: FBXO7 NM_012179.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: -0.464

Genes affected

FBXO7 (HGNC:13586): (F-box protein 7) 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 it may play a role in regulation of hematopoiesis. Alternatively spliced transcript variants of this gene have been identified with the full-length natures of only some variants being determined. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012093067).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000519 (79/152294) while in subpopulation NFE AF= 0.000911 (62/68020). AF 95% confidence interval is 0.000729. There are 0 homozygotes in gnomad4. There are 36 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBXO7	NM_012179.4	c.1453G>A	p.Val485Ile	missense_variant	9/9	ENST00000266087.12
FBXO7	NM_001033024.2	c.1216G>A	p.Val406Ile	missense_variant	9/9
FBXO7	NM_001257990.2	c.1111G>A	p.Val371Ile	missense_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBXO7	ENST00000266087.12	c.1453G>A	p.Val485Ile	missense_variant	9/9	1	NM_012179.4	P2

Frequencies

GnomAD3 genomes AF: 0.000519 AC: 79 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000911

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000342 AC: 86 AN: 251452 Hom.: 0 AF XY: 0.000339 AC XY: 46 AN XY: 135892

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000289

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: 0.000633

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000741 AC: 1083 AN: 1461888 Hom.: 2 Cov.: 31 AF XY: 0.000707 AC XY: 514 AN XY: 727242

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000930

Gnomad4 OTH exome AF: 0.000464

GnomAD4 genome AF: 0.000519 AC: 79 AN: 152294 Hom.: 0 Cov.: 32 AF XY: 0.000483 AC XY: 36 AN XY: 74466

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000911

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000725 Hom.: 0

Bravo AF: 0.000502

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000296 AC: 36

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000927

EpiControl AF: 0.000889

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Parkinsonian-pyramidal syndrome Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 26, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 10, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 05, 2022	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 485 of the FBXO7 protein (p.Val485Ile). This variant is present in population databases (rs141286570, gnomAD 0.06%). This missense change has been observed in individual(s) with Parkinson's disease (PMID: 27294386). ClinVar contains an entry for this variant (Variation ID: 597905). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt FBXO7 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 10, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 24, 2022	Identified in the heterozygous state in an individual with Parkinson disease in the published literature; however, a second FBX07 variant was not identified (Gorostidi et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27294386) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	0.0020
Dann	Benign	0.38
DEOGEN2	Benign	0.029	T;.;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.069	T;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.012	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.42	N;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.37	N;.;N
REVEL	Benign	0.037
Sift	Benign	1.0	T;.;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.084
MVP		0.29
MPC		0.055
ClinPred		0.0025	T
GERP RS		-6.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.012
gMVP		0.25

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: rs141286570; hg19: chr22-32894401;