rs142814111
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_ModerateBP6BP7
The NM_001278716.2(FBXL4):c.936G>A(p.Gln312=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,613,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000048 ( 0 hom. )
Consequence
FBXL4
NM_001278716.2 synonymous
NM_001278716.2 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 1.25
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 Likely_benign. Variant got -2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.44).
BP6
Variant 6-98905593-C-T is Benign according to our data. Variant chr6-98905593-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 437659.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}. Variant chr6-98905593-C-T is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=1.25 with no splicing effect.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| FBXL4 | NM_001278716.2 | c.936G>A | p.Gln312= | synonymous_variant | 6/10 | ENST00000369244.7 | NP_001265645.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| FBXL4 | ENST00000369244.7 | c.936G>A | p.Gln312= | synonymous_variant | 6/10 | 1 | NM_001278716.2 | ENSP00000358247 | P1 | |
| FBXL4 | ENST00000229971.2 | c.936G>A | p.Gln312= | synonymous_variant | 5/9 | 1 | ENSP00000229971 | P1 |
Frequencies
GnomAD3 genomes 0.0000986 AC: 15AN: 152080Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000279 AC: 7AN: 251294Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135812
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GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461726Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4AN XY: 727166
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GnomAD4 genome 0.0000986 AC: 15AN: 152080Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7AN XY: 74304
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
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.936G>A (NP_036292.2:p.Gln312=) [GRCH38: NC_000006.12:g.98905593C>T] 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. 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 Uncertain Significance - Conflicting Evidence. - |
not provided Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 14, 2023 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
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DANN
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Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at