rs17058965
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Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2
The NM_001278716.2(FBXL4):āc.429A>Gā(p.Leu143Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000833 in 1,614,162 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā ā ).
Frequency
Genomes: š 0.0044 ( 5 hom., cov: 32)
Exomes š: 0.00046 ( 5 hom. )
Consequence
FBXL4
NM_001278716.2 synonymous
NM_001278716.2 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 1.37
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 -16 ACMG points.
BP6
Variant 6-98926560-T-C is Benign according to our data. Variant chr6-98926560-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 382986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-98926560-T-C is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00438 (667/152302) while in subpopulation AFR AF= 0.0154 (640/41556). AF 95% confidence interval is 0.0144. There are 5 homozygotes in gnomad4. There are 307 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 5 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FBXL4 | NM_001278716.2 | c.429A>G | p.Leu143Leu | synonymous_variant | 4/10 | ENST00000369244.7 | NP_001265645.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FBXL4 | ENST00000369244.7 | c.429A>G | p.Leu143Leu | synonymous_variant | 4/10 | 1 | NM_001278716.2 | ENSP00000358247.1 | ||
FBXL4 | ENST00000229971.2 | c.429A>G | p.Leu143Leu | synonymous_variant | 3/9 | 1 | ENSP00000229971.1 |
Frequencies
GnomAD3 genomes AF: 0.00438 AC: 666AN: 152184Hom.: 5 Cov.: 32
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GnomAD3 exomes AF: 0.00119 AC: 298AN: 251358Hom.: 2 AF XY: 0.000861 AC XY: 117AN XY: 135838
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GnomAD4 exome AF: 0.000463 AC: 677AN: 1461860Hom.: 5 Cov.: 31 AF XY: 0.000402 AC XY: 292AN XY: 727224
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GnomAD4 genome AF: 0.00438 AC: 667AN: 152302Hom.: 5 Cov.: 32 AF XY: 0.00412 AC XY: 307AN XY: 74484
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | GeneDx | Nov 22, 2019 | - - |
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | - - |
Mitochondrial DNA depletion syndrome 13 Benign:1
Likely 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.429A>G (NP_036292.2:p.Leu143=) [GRCH38: NC_000006.12:g.98926560T>C] variant in FBXL4 gene is interpretated to be a Likely Benign based on ACMG guidelines (PMID: 25741868). This variant meets one or more of the following evidence codes reported in the ACMG-guideline. BS1:The minor allele frequency of this allele is high for Mitochondrial DNA depletion syndrome 13. BP4:Computational evidence/predictors indicate no impact on the FBXL4 structure, function, or protein-protein interaction. BP5:The variant is found in a case with alternate cuase. BP7:The variant is silent with non predicted splice impact. Based on this evidence code ClinGen Pathogenicity Calculator (PMID:28081714) suggested that the variant is Likely Benign. - |
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
DS_AG_spliceai
Position offset: 26
Find out detailed SpliceAI scores and Pangolin per-transcript scores at