5-15936737-C-T

Variant summary

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

The NM_012304.5(FBXL7):​c.1027C>T​(p.Arg343Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000622 in 1,608,854 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

FBXL7
NM_012304.5 missense

Scores

5
9
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.95
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/exons MANE Protein UniProt
FBXL7NM_012304.5 linkuse as main transcriptc.1027C>T p.Arg343Trp missense_variant 4/4 ENST00000504595.2 NP_036436.1 Q9UJT9-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FBXL7ENST00000504595.2 linkuse as main transcriptc.1027C>T p.Arg343Trp missense_variant 4/41 NM_012304.5 ENSP00000423630.1 Q9UJT9-1
FBXL7ENST00000510662.1 linkuse as main transcriptc.886C>T p.Arg296Trp missense_variant 4/41 ENSP00000425184.1 Q9UJT9-2
FBXL7ENST00000329673.8 linkuse as main transcriptc.901C>T p.Arg301Trp missense_variant 2/22 ENSP00000329632.8 J3KNM9

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152238
Hom.:
0
Cov.:
33
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000832
AC:
2
AN:
240448
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
131248
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.000101
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000908
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000549
AC:
8
AN:
1456498
Hom.:
0
Cov.:
31
AF XY:
0.00000414
AC XY:
3
AN XY:
724646
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.0000384
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000201
Gnomad4 NFE exome
AF:
0.00000450
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152356
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74510
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:
0.0000294
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000117
AC:
1
ExAC
AF:
0.0000165
AC:
2

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsSep 29, 2022The c.1027C>T (p.R343W) alteration is located in exon 4 (coding exon 4) of the FBXL7 gene. This alteration results from a C to T substitution at nucleotide position 1027, causing the arginine (R) at amino acid position 343 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
Pathogenic
0.85
BayesDel_addAF
Pathogenic
0.18
D
BayesDel_noAF
Uncertain
0.030
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.12
T;.;.
Eigen
Uncertain
0.37
Eigen_PC
Uncertain
0.28
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.99
D;D;D
M_CAP
Benign
0.035
D
MetaRNN
Uncertain
0.45
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.4
M;.;.
PrimateAI
Pathogenic
0.86
D
PROVEAN
Benign
-1.7
N;N;.
REVEL
Uncertain
0.39
Sift
Uncertain
0.010
D;D;.
Sift4G
Uncertain
0.016
D;D;D
Polyphen
1.0
D;.;.
Vest4
0.77
MVP
0.54
MPC
1.8
ClinPred
0.88
D
GERP RS
4.5
Varity_R
0.28
gMVP
0.79

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: rs375745885; hg19: chr5-15936846; COSMIC: COSV61648362; COSMIC: COSV61648362; API