rs751643380
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_001278716.2(FBXL4):c.1156C>T(p.His386Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000048 ( 0 hom. )
Consequence
FBXL4
NM_001278716.2 missense
NM_001278716.2 missense
Scores
2
4
12
Clinical Significance
Conservation
PhyloP100: 9.60
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.759
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FBXL4 | NM_001278716.2 | c.1156C>T | p.His386Tyr | missense_variant | 7/10 | ENST00000369244.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBXL4 | ENST00000369244.7 | c.1156C>T | p.His386Tyr | missense_variant | 7/10 | 1 | NM_001278716.2 | P1 | |
FBXL4 | ENST00000229971.2 | c.1156C>T | p.His386Tyr | missense_variant | 6/9 | 1 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152126Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000798 AC: 2AN: 250726Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135460
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GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461644Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3AN XY: 727116
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152126Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74320
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Mitochondrial DNA depletion syndrome 13 Uncertain:1
Uncertain significance, criteria provided, single submitter | reference population | Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine | Aug 10, 2017 | The NM_012160.4:c.1156C>T (NP_036292.2:p.His386Tyr) [GRCH38: NC_000006.12:g.98899429G>A] variant in FBXL4 gene is interpretated to be a Uncertain Significance - Insufficient 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. PP3:Computational evidence/predictors indicate the variant has deleterious effect on FBXL4 structure, function, or protein-protein interaction. Based on this evidence code ClinGen Pathogenicity Calculator (PMID:28081714) suggested that the variant is Uncertain Significance - Insufficient Evidence. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 14, 2022 | This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 386 of the FBXL4 protein (p.His386Tyr). This variant is present in population databases (rs751643380, 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: 437705). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FBXL4 protein function. 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D
MetaSVM
Benign
T
MutationAssessor
Benign
L;L
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Benign
Sift
Benign
T;T
Sift4G
Benign
T;T
Polyphen
D;D
Vest4
MutPred
Loss of catalytic residue at L388 (P = 0.079);Loss of catalytic residue at L388 (P = 0.079);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at