22-32479203-G-A

Position:

• chr22-32479203-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000266087.12(FBXO7):​c.345G>A​(p.Met115Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.404 in 1,613,402 control chromosomes in the GnomAD database, including 136,759 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar.

• Frequency:
  • Genomes: 𝑓 0.42 (13649 hom., cov: 30)
  • Exomes 𝑓: 0.40 (123110 hom.)
• Consequence: FBXO7 ENST00000266087.12 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.0270

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.0905507E-6).
• BP6: Variant 22-32479203-G-A is Benign according to our data. Variant chr22-32479203-G-A is described in ClinVar as [Benign]. Clinvar id is 195275.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-32479203-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.668 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBXO7	NM_012179.4	c.345G>A	p.Met115Ile	missense_variant	2/9	ENST00000266087.12	NP_036311.3
FBXO7	NM_001257990.2	c.3G>A	p.Met1?	start_lost	2/9		NP_001244919.1
FBXO7	NM_001033024.2	c.108G>A	p.Met36Ile	missense_variant	2/9		NP_001028196.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBXO7	ENST00000266087.12	c.345G>A	p.Met115Ile	missense_variant	2/9	1	NM_012179.4	ENSP00000266087	P2

Frequencies

GnomAD3 genomes AF: 0.416 AC: 63089 AN: 151522 Hom.: 13628 Cov.: 30

Gnomad AFR AF: 0.387

Gnomad AMI AF: 0.346

Gnomad AMR AF: 0.505

Gnomad ASJ AF: 0.418

Gnomad EAS AF: 0.687

Gnomad SAS AF: 0.460

Gnomad FIN AF: 0.496

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.380

Gnomad OTH AF: 0.398

GnomAD3 exomes AF: 0.453 AC: 113761 AN: 251364 Hom.: 27224 AF XY: 0.447 AC XY: 60780 AN XY: 135856

Gnomad AFR exome AF: 0.388

Gnomad AMR exome AF: 0.606

Gnomad ASJ exome AF: 0.409

Gnomad EAS exome AF: 0.687

Gnomad SAS exome AF: 0.474

Gnomad FIN exome AF: 0.481

Gnomad NFE exome AF: 0.371

Gnomad OTH exome AF: 0.429

GnomAD4 exome AF: 0.402 AC: 588283 AN: 1461758 Hom.: 123110 Cov.: 49 AF XY: 0.405 AC XY: 294181 AN XY: 727172

Gnomad4 AFR exome AF: 0.380

Gnomad4 AMR exome AF: 0.595

Gnomad4 ASJ exome AF: 0.406

Gnomad4 EAS exome AF: 0.736

Gnomad4 SAS exome AF: 0.466

Gnomad4 FIN exome AF: 0.469

Gnomad4 NFE exome AF: 0.374

Gnomad4 OTH exome AF: 0.416

GnomAD4 genome AF: 0.416 AC: 63145 AN: 151644 Hom.: 13649 Cov.: 30 AF XY: 0.425 AC XY: 31503 AN XY: 74086

Gnomad4 AFR AF: 0.387

Gnomad4 AMR AF: 0.505

Gnomad4 ASJ AF: 0.418

Gnomad4 EAS AF: 0.687

Gnomad4 SAS AF: 0.459

Gnomad4 FIN AF: 0.496

Gnomad4 NFE AF: 0.380

Gnomad4 OTH AF: 0.401

Alfa AF: 0.392 Hom.: 29586

Bravo AF: 0.418

TwinsUK AF: 0.361 AC: 1340

ALSPAC AF: 0.373 AC: 1437

ESP6500AA AF: 0.372 AC: 1640

ESP6500EA AF: 0.372 AC: 3202

ExAC AF: 0.440 AC: 53403

Asia WGS AF: 0.594 AC: 2063 AN: 3478

EpiCase AF: 0.374

EpiControl AF: 0.375

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Parkinsonian-pyramidal syndrome Benign:5

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Apr 22, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 17, 2018	This variant is associated with the following publications: (PMID: 23222517) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

May 21, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	2.6
DANN	Benign	0.39
DEOGEN2	Benign	0.033	T;.;.;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.082	T;T;D;D
MetaRNN	Benign	0.0000021	T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-2.0	N;.;.;.
MutationTaster	Benign	5.5e-25	P;P;P
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.17	N;N;N;N
REVEL	Benign	0.089
Sift	Benign	0.22	T;T;T;T
Sift4G	Benign	0.32	T;T;T;T
Polyphen		0.0	B;B;.;.
Vest4		0.010
MutPred		0.053		Gain of glycosylation at S114 (P = 0.0537);.;.;.;
MPC		0.070
ClinPred		0.0057	T
GERP RS		-3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.031
gMVP		0.078

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: rs11107; hg19: chr22-32875190; COSMIC: COSV56678154;