Genetic Variant FBXO7:p.Leu7Phe (chr22-32475021-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_012179.4(FBXO7):c.19C>T(p.Leu7Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000721 in 1,387,674 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L7V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

FBXO7
NM_012179.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0770

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: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

FBXO7 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16647801).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012179.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FBXO7	NM_012179.4	MANE Select	c.19C>T	p.Leu7Phe	missense	Exon 1 of 9	NP_036311.3
FBXO7	NM_001033024.2		c.-341C>T		upstream_gene	N/A	NP_001028196.1	Q9Y3I1-2
FBXO7	NM_001257990.2		c.-598C>T		upstream_gene	N/A	NP_001244919.1	Q9Y3I1-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FBXO7	ENST00000266087.12	TSL:1 MANE Select	c.19C>T	p.Leu7Phe	missense	Exon 1 of 9	ENSP00000266087.7	Q9Y3I1-1
FBXO7	ENST00000886524.1		c.19C>T	p.Leu7Phe	missense	Exon 1 of 10	ENSP00000556583.1
FBXO7	ENST00000920428.1		c.19C>T	p.Leu7Phe	missense	Exon 1 of 9	ENSP00000590487.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.21e-7

AC:

AN:

1387674

Hom.:

Cov.:

AF XY:

0.00000146

AC XY:

AN XY:

684704

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30730

American (AMR)

AF:

0.00

AC:

AN:

35538

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25032

East Asian (EAS)

AF:

0.00

AC:

AN:

35322

South Asian (SAS)

AF:

0.00

AC:

AN:

78766

European-Finnish (FIN)

AF:

0.00

AC:

AN:

43388

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4116

European-Non Finnish (NFE)

AF:

9.28e-7

AC:

AN:

1077188

Other (OTH)

AF:

0.00

AC:

AN:

57594

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.052

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.19

FATHMM_MKL

Benign

0.49

LIST_S2

Benign

0.75

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.17

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.7

PhyloP100

-0.077

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.52

REVEL

Benign

0.038

Sift

Benign

0.26

Sift4G

Uncertain

0.016

Polyphen

0.66

Vest4

0.24

MutPred

0.31

Loss of disorder (P = 0.0406)

MVP

0.56

MPC

0.073

ClinPred

0.56

GERP RS

2.1

PromoterAI

-0.0068

Neutral

(source)

Varity_R

0.087

gMVP

0.44

Mutation Taster

=84/16

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over