rs1011676
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1
The NM_001278716.2(FBXL4):c.465C>T(p.Leu155=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0718 in 1,613,406 control chromosomes in the GnomAD database, including 4,817 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.054 ( 333 hom., cov: 32)
Exomes 𝑓: 0.074 ( 4484 hom. )
Consequence
FBXL4
NM_001278716.2 synonymous
NM_001278716.2 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.336
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 Benign. Variant got -21 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.49).
BP6
?
Variant 6-98926524-G-A is Benign according to our data. Variant chr6-98926524-G-A is described in ClinVar as [Benign]. Clinvar id is 260209.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-98926524-G-A is described in Lovd as [Benign].
BP7
?
Synonymous conserved (PhyloP=0.336 with no splicing effect.
BA1
?
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.08 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FBXL4 | NM_001278716.2 | c.465C>T | p.Leu155= | synonymous_variant | 4/10 | ENST00000369244.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBXL4 | ENST00000369244.7 | c.465C>T | p.Leu155= | synonymous_variant | 4/10 | 1 | NM_001278716.2 | P1 | |
FBXL4 | ENST00000229971.2 | c.465C>T | p.Leu155= | synonymous_variant | 3/9 | 1 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0540 AC: 8218AN: 152108Hom.: 333 Cov.: 32
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GnomAD3 exomes AF: 0.0595 AC: 14914AN: 250634Hom.: 574 AF XY: 0.0626 AC XY: 8473AN XY: 135424
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GnomAD4 exome AF: 0.0737 AC: 107688AN: 1461180Hom.: 4484 Cov.: 32 AF XY: 0.0742 AC XY: 53918AN XY: 726774
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GnomAD4 genome ? AF: 0.0540 AC: 8218AN: 152226Hom.: 333 Cov.: 32 AF XY: 0.0539 AC XY: 4013AN XY: 74430
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ClinVar
Significance: Benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 02, 2015 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Benign, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Feb 26, 2016 | - - |
Mitochondrial DNA depletion syndrome 13 Benign:1
Benign, 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.465C>T (NP_036292.2:p.Leu155=) [GRCH38: NC_000006.12:g.98926524G>A] variant in FBXL4 gene is interpretated to be a Benign - Stand Alone based on ACMG guidelines (PMID: 25741868). This variant meets one or more of the following evidence codes reported in the ACMG-guideline. BA1:Minor allele frequency is too high for the Mitochondrial DNA depletion syndrome 13. BS2:Observation of the variant is in controls is inconsistent with penetrance of Mitochondrial DNA depletion syndrome 13. 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 Benign - Stand Alone. - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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