rs779731686

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001278716.2(FBXL4):​c.1721C>T​(p.Pro574Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000317 in 1,607,186 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P574P) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

FBXL4
NM_001278716.2 missense

Scores

1
4
14

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 7.78
Variant links:
Genes affected
FBXL4 (HGNC:13601): (F-box and leucine rich repeat protein 4) This gene encodes a member of the F-box protein family, which are characterized by an approximately 40 amino acid motif, the F-box. F-box proteins constitute one subunit of modular E3 ubiquitin ligase complexes, called SCF complexes, which function in phosphorylation-dependent ubiquitination. The F-box domain mediates protein-protein interactions and binds directly to S-phase kinase-associated protein 1. In addition to an F-box domain, the encoded protein contains at least 9 tandem leucine-rich repeats. The ubiquitin ligase complex containing the encoded protein may function in cell-cycle control by regulating levels of lysine-specific demethylase 4A. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.22490546).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FBXL4NM_001278716.2 linkc.1721C>T p.Pro574Leu missense_variant Exon 10 of 10 ENST00000369244.7 NP_001265645.1 Q9UKA2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FBXL4ENST00000369244.7 linkc.1721C>T p.Pro574Leu missense_variant Exon 10 of 10 1 NM_001278716.2 ENSP00000358247.1 Q9UKA2
FBXL4ENST00000229971.2 linkc.1721C>T p.Pro574Leu missense_variant Exon 9 of 9 1 ENSP00000229971.1 Q9UKA2

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
151908
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:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000328
AC:
8
AN:
243568
Hom.:
0
AF XY:
0.0000379
AC XY:
5
AN XY:
131920
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000309
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000112
Gnomad SAS exome
AF:
0.0000341
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000361
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000337
AC:
49
AN:
1455278
Hom.:
0
Cov.:
31
AF XY:
0.0000373
AC XY:
27
AN XY:
723992
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000472
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000253
Gnomad4 SAS exome
AF:
0.0000353
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000378
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000132
AC:
2
AN:
151908
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74172
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000564
Hom.:
0
ExAC
AF:
0.0000412
AC:
5
EpiCase
AF:
0.000164
EpiControl
AF:
0.0000594

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Mitochondrial DNA depletion syndrome 13 Uncertain:2
Dec 08, 2022
Revvity Omics, Revvity
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 10, 2017
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: reference population

The NM_012160.4:c.1721C>T (NP_036292.2:p.Pro574Leu) [GRCH38: NC_000006.12:g.98874423G>A] variant in FBXL4 gene is interpretated to be a Uncertain Significance - Conflicting Evidence based on ACMG guidelines (PMID: 25741868). This variant meets one or more of the following evidence codes reported in the ACMG-guideline. PM2:This variant is absent in key population databases. BP4:Computational evidence/predictors indicate no impact on the FBXL4 structure, function, or protein-protein interaction. Based on this evidence code ClinGen Pathogenicity Calculator (PMID:28081714) suggested that the variant is Uncertain Significance - Conflicting Evidence. -

not provided Uncertain:2
Jan 11, 2023
Mayo Clinic Laboratories, Mayo Clinic
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

BP4, PM2 -

Sep 24, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 574 of the FBXL4 protein (p.Pro574Leu). This variant is present in population databases (rs779731686, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with FBXL4-related conditions. ClinVar contains an entry for this variant (Variation ID: 437799). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt FBXL4 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases Uncertain:1
Aug 23, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1721C>T (p.P574L) alteration is located in exon 9 (coding exon 7) of the FBXL4 gene. This alteration results from a C to T substitution at nucleotide position 1721, causing the proline (P) at amino acid position 574 to be replaced by a leucine (L). 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
Benign
0.21
BayesDel_addAF
Benign
-0.25
T
BayesDel_noAF
Benign
-0.38
CADD
Benign
22
DANN
Benign
0.97
DEOGEN2
Benign
0.23
T;T
Eigen
Uncertain
0.30
Eigen_PC
Uncertain
0.39
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.88
.;D
M_CAP
Benign
0.024
T
MetaRNN
Benign
0.22
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.6
L;L
PrimateAI
Uncertain
0.69
T
PROVEAN
Benign
-1.6
N;N
REVEL
Benign
0.16
Sift
Benign
0.063
T;T
Sift4G
Benign
0.56
T;T
Polyphen
0.82
P;P
Vest4
0.20
MutPred
0.55
Loss of disorder (P = 0.0795);Loss of disorder (P = 0.0795);
MVP
0.43
MPC
0.29
ClinPred
0.19
T
GERP RS
5.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.12
gMVP
0.56

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
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: rs779731686; hg19: chr6-99322299; COSMIC: COSV100014157; API