chr5-15928354-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_012304.5(FBXL7):​c.592C>T​(p.Arg198Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000341 in 1,613,770 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

FBXL7
NM_012304.5 missense

Scores

3
10
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.50
Variant links:
Genes affected
FBXL7 (HGNC:13604): (F-box and leucine rich repeat protein 7) This gene encodes a member of the F-box protein family which is characterized by a 42-48 amino acid motif, the F-box, which binds to the S-phase kinase-associated protein 1 (Skp1) protein. The F-box proteins constitute one of the four subunits of E3 ubiquitin protein ligases called SCFs (SKP1-Cul1-F-box), which play a role in phosphorylation-dependent ubiquitination of proteins. The F-box proteins are divided into 3 subfamilies based on the other domain in the protein: F-box proteins that also have a WD-40 domain (Fbws subfamily), F-box proteins that also have leucine-rich repeats (Fbls subfamily) and F-box proteins that contain other motifs or lack known protein-interaction domains (Fbxs subfamily). The protein encoded by this gene belongs to the Fbls subfamily. Alternative splicing results in multiple transcript variants of this gene. [provided by RefSeq, May 2013]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FBXL7NM_012304.5 linkc.592C>T p.Arg198Trp missense_variant Exon 3 of 4 ENST00000504595.2 NP_036436.1 Q9UJT9-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FBXL7ENST00000504595.2 linkc.592C>T p.Arg198Trp missense_variant Exon 3 of 4 1 NM_012304.5 ENSP00000423630.1 Q9UJT9-1
FBXL7ENST00000510662.1 linkc.451C>T p.Arg151Trp missense_variant Exon 3 of 4 1 ENSP00000425184.1 Q9UJT9-2
FBXL7ENST00000329673.8 linkc.466C>T p.Arg156Trp missense_variant Exon 1 of 2 2 ENSP00000329632.8 J3KNM9

Frequencies

GnomAD3 genomes
AF:
0.0000328
AC:
5
AN:
152230
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000735
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000445
AC:
11
AN:
247256
Hom.:
0
AF XY:
0.0000595
AC XY:
8
AN XY:
134364
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
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:
0.0000987
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000342
AC:
50
AN:
1461540
Hom.:
0
Cov.:
36
AF XY:
0.0000358
AC XY:
26
AN XY:
727052
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000387
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.0000328
AC:
5
AN:
152230
Hom.:
0
Cov.:
32
AF XY:
0.0000403
AC XY:
3
AN XY:
74392
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000735
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000823
Hom.:
0
Bravo
AF:
0.0000416
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000237
AC:
2
ExAC
AF:
0.0000331
AC:
4

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jan 26, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.592C>T (p.R198W) alteration is located in exon 3 (coding exon 3) of the FBXL7 gene. This alteration results from a C to T substitution at nucleotide position 592, causing the arginine (R) at amino acid position 198 to be replaced by a tryptophan (W). 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
Uncertain
0.37
BayesDel_addAF
Benign
-0.039
T
BayesDel_noAF
Benign
-0.10
CADD
Uncertain
26
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.23
T;.;.
Eigen
Uncertain
0.59
Eigen_PC
Uncertain
0.51
FATHMM_MKL
Uncertain
0.84
D
LIST_S2
Uncertain
0.94
D;D;D
M_CAP
Benign
0.057
D
MetaRNN
Uncertain
0.64
D;D;D
MetaSVM
Benign
-0.50
T
MutationAssessor
Pathogenic
3.1
M;.;.
PrimateAI
Pathogenic
0.80
T
PROVEAN
Uncertain
-3.1
D;D;D
REVEL
Uncertain
0.36
Sift
Uncertain
0.0010
D;D;D
Sift4G
Uncertain
0.0060
D;D;D
Polyphen
1.0
D;.;.
Vest4
0.81
MVP
0.85
MPC
1.7
ClinPred
0.88
D
GERP RS
4.5
Varity_R
0.42
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs369795247; hg19: chr5-15928463; COSMIC: COSV61641844; API