rs200440128
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The ENST00000369244.7(FBXL4):c.64C>T(p.Arg22Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000162 in 1,613,916 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 Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00017 ( 0 hom. )
Consequence
FBXL4
ENST00000369244.7 stop_gained
ENST00000369244.7 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 7.63
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 Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 106 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 6-98926925-G-A is Pathogenic according to our data. Variant chr6-98926925-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 209153.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-98926925-G-A is described in Lovd as [Pathogenic]. Variant chr6-98926925-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FBXL4 | NM_001278716.2 | c.64C>T | p.Arg22Ter | stop_gained | 4/10 | ENST00000369244.7 | NP_001265645.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FBXL4 | ENST00000369244.7 | c.64C>T | p.Arg22Ter | stop_gained | 4/10 | 1 | NM_001278716.2 | ENSP00000358247 | P1 | |
FBXL4 | ENST00000229971.2 | c.64C>T | p.Arg22Ter | stop_gained | 3/9 | 1 | ENSP00000229971 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152080Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000597 AC: 15AN: 251138Hom.: 0 AF XY: 0.0000663 AC XY: 9AN XY: 135726
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GnomAD4 exome AF: 0.000174 AC: 254AN: 1461836Hom.: 0 Cov.: 32 AF XY: 0.000177 AC XY: 129AN XY: 727216
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GnomAD4 genome AF: 0.0000460 AC: 7AN: 152080Hom.: 0 Cov.: 33 AF XY: 0.0000539 AC XY: 4AN XY: 74274
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:13
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 15, 2023 | This sequence change creates a premature translational stop signal (p.Arg22*) in the FBXL4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FBXL4 are known to be pathogenic (PMID: 23993193, 23993194, 25868664). This variant is present in population databases (rs200440128, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with clinical features of FBXL4-related conditions (PMID: 27290639, 27743463). ClinVar contains an entry for this variant (Variation ID: 209153). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Aug 29, 2017 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes | Jul 27, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jul 31, 2023 | PM2_moderate, PM3, PVS1 - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 18, 2022 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27290639, 27743463, 28940506, 26633545, 30804983, 32525278, 33726816) - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 02, 2016 | - - |
Mitochondrial DNA depletion syndrome 13 Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 23, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine | Jan 28, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 27, 2014 | This nonsense variant is categorized as deleterious according to ACMG guidelines (PMID:18414213) and was found once in our laboratory homozygous in a 32-year-old male with intellectual disability, hypotonia, dragging of right foot when walking, tremors, dysmorphisms, hyperextensibility, failure to thrive, amblyopia, myopia, mitral valve prolapse, scoliosis, serial episodes of lactic acidosis, white matter abnormalities. Variant pathogenic in recessive state; heterozygotes are carriers. - |
Pathogenic, criteria provided, single submitter | clinical testing | Department of Molecular and Human Genetics, Baylor College of Medicine | Apr 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine | Aug 10, 2017 | The NM_012160.4:c.64C>T (NP_036292.2:p.Arg22Ter) [GRCH38: NC_000006.12:g.98926925G>A] variant in FBXL4 gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:27743463 ; 27290639 . This variant meets one or more of the following evidence codes reported in the ACMG-guideline. PVS1:This variant is a predcted null variant in FBXL4 where loss of function is a known mechanism of disease. PM2:This variant is absent in key population databases. PM3:Detected in trans with a pathogenic variant for Mitochondrial DNA depletion syndrome 13 which is a recessive disorder. PP4:Patient’s phenotype or family history is highly specific for FBXL4. PP5:Reputable source(s) suggest that the variant is pathogenic. Based on this evidence code ClinGen Pathogenicity Calculator (PMID:28081714) suggested that the variant is Pathogenic. - |
Neurodevelopmental delay Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille | - | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 24, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;A
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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