chr22-32475133-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_012179.4(FBXO7):c.122+9G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00546 in 1,540,668 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0039 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0056 ( 25 hom. )

Consequence

FBXO7
NM_012179.4 intron

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: -0.0480

Publications

0 publications found

Variant links:

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]

FBXO7 Gene-Disease associations (from GenCC):

parkinsonian-pyramidal syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp

FBXO7 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.74).

BP6

Variant 22-32475133-G-A is Benign according to our data. Variant chr22-32475133-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 341307.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00393 (598/152318) while in subpopulation NFE AF = 0.00706 (480/68012). AF 95% confidence interval is 0.00654. There are 3 homozygotes in GnomAd4. There are 260 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
FBXO7	NM_012179.4 link	c.122+9G>A	intron_variant	Intron 1 of 8	ENST00000266087.12	NP_036311.3	Q9Y3I1-1
FBXO7	NM_001033024.2 link	c.-229G>A	upstream_gene_variant			NP_001028196.1	Q9Y3I1-2
FBXO7	NM_001257990.2 link	c.-486G>A	upstream_gene_variant			NP_001244919.1	Q9Y3I1-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBXO7	ENST00000266087.12 link	c.122+9G>A		intron_variant	Intron 1 of 8	1	NM_012179.4	ENSP00000266087.7		Q9Y3I1-1

Frequencies

GnomAD3 genomes

AF:

0.00394

AC:

599

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00137

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.00190

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.00103

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.00706

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00311

AC:

425

AN:

136722

AF XY:

0.00308

show subpopulations

Gnomad AFR exome

AF:

0.000548

Gnomad AMR exome

AF:

0.000747

Gnomad ASJ exome

AF:

0.00138

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00162

Gnomad NFE exome

AF:

0.00706

Gnomad OTH exome

AF:

0.00249

GnomAD4 exome

AF:

0.00563

AC:

7820

AN:

1388350

Hom.:

Cov.:

AF XY:

0.00546

AC XY:

3736

AN XY:

684556

show subpopulations

African (AFR)

AF:

0.000856

AC:

AN:

30358

American (AMR)

AF:

0.000792

AC:

AN:

35362

Ashkenazi Jewish (ASJ)

AF:

0.00193

AC:

AN:

24918

East Asian (EAS)

AF:

0.00

AC:

AN:

35086

South Asian (SAS)

AF:

0.000510

AC:

AN:

78482

European-Finnish (FIN)

AF:

0.00185

AC:

AN:

46364

Middle Eastern (MID)

AF:

0.00179

AC:

AN:

4464

European-Non Finnish (NFE)

AF:

0.00686

AC:

7381

AN:

1075850

Other (OTH)

AF:

0.00353

AC:

203

AN:

57466

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

444

889

1333

1778

2222

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

292

584

876

1168

1460

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00393

AC:

598

AN:

152318

Hom.:

Cov.:

AF XY:

0.00349

AC XY:

260

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.00137

AC:

AN:

41582

American (AMR)

AF:

0.00189

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.000414

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00103

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00706

AC:

480

AN:

68012

Other (OTH)

AF:

0.00189

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

127

159

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00507

Hom.:

Bravo

AF:

0.00384

Asia WGS

AF:

0.000289

AC:

AN:

3474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Parkinsonian-pyramidal syndrome

Uncertain:1Benign:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 19, 2016

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified

Benign:1

Feb 03, 2017

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

FBXO7: BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

6.9

(source)

DANN

Benign

0.95

PhyloP100

-0.048

PromoterAI

0.056

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over