rs199540184

Variant summary

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

The NM_001278716.2(FBXL4):ā€‹c.1069A>Gā€‹(p.Asn357Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,614,054 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.000033 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000055 ( 0 hom. )

Consequence

FBXL4
NM_001278716.2 missense

Scores

1
7
11

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 7.67
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 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
FBXL4NM_001278716.2 linkc.1069A>G p.Asn357Asp missense_variant 6/10 ENST00000369244.7 NP_001265645.1 Q9UKA2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FBXL4ENST00000369244.7 linkc.1069A>G p.Asn357Asp missense_variant 6/101 NM_001278716.2 ENSP00000358247.1 Q9UKA2
FBXL4ENST00000229971.2 linkc.1069A>G p.Asn357Asp missense_variant 5/91 ENSP00000229971.1 Q9UKA2

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152176
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000327
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000159
AC:
4
AN:
251386
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135862
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000116
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000547
AC:
8
AN:
1461760
Hom.:
0
Cov.:
33
AF XY:
0.00000275
AC XY:
2
AN XY:
727174
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000157
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000328
AC:
5
AN:
152294
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74492
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000327
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000416
ExAC
AF:
0.0000247
AC:
3

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:2
Uncertain significance, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 17, 2023Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FBXL4 protein function. ClinVar contains an entry for this variant (Variation ID: 437681). This variant has not been reported in the literature in individuals affected with FBXL4-related conditions. This variant is present in population databases (rs199540184, gnomAD 0.01%). This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 357 of the FBXL4 protein (p.Asn357Asp). 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. -
Mitochondrial DNA depletion syndrome 13 Uncertain:1
Uncertain significance, criteria provided, single submitterreference populationWong Mito Lab, Molecular and Human Genetics, Baylor College of MedicineAug 10, 2017The NM_012160.4:c.1069A>G (NP_036292.2:p.Asn357Asp) [GRCH38: NC_000006.12:g.98905460T>C] 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.42
BayesDel_addAF
Benign
-0.33
T
BayesDel_noAF
Benign
-0.49
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.058
T;T
Eigen
Uncertain
0.43
Eigen_PC
Uncertain
0.51
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.88
.;D
M_CAP
Benign
0.011
T
MetaRNN
Uncertain
0.51
D;D
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.9
M;M
PrimateAI
Uncertain
0.76
T
PROVEAN
Benign
-1.9
N;N
REVEL
Benign
0.13
Sift
Benign
0.20
T;T
Sift4G
Benign
0.44
T;T
Polyphen
0.89
P;P
Vest4
0.90
MVP
0.50
MPC
0.089
ClinPred
0.47
T
GERP RS
5.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.35
gMVP
0.55

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: rs199540184; hg19: chr6-99353336; API