rs201149065
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_001278716.2(FBXL4):āc.526T>Cā(p.Trp176Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000739 in 1,597,108 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 (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W176S) has been classified as Uncertain significance.
Frequency
Consequence
NM_001278716.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FBXL4 | NM_001278716.2 | c.526T>C | p.Trp176Arg | missense_variant | 5/10 | ENST00000369244.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBXL4 | ENST00000369244.7 | c.526T>C | p.Trp176Arg | missense_variant | 5/10 | 1 | NM_001278716.2 | P1 | |
FBXL4 | ENST00000229971.2 | c.526T>C | p.Trp176Arg | missense_variant | 4/9 | 1 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152192Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000521 AC: 12AN: 230222Hom.: 0 AF XY: 0.0000482 AC XY: 6AN XY: 124602
GnomAD4 exome AF: 0.0000782 AC: 113AN: 1444798Hom.: 0 Cov.: 31 AF XY: 0.0000738 AC XY: 53AN XY: 717954
GnomAD4 genome ? AF: 0.0000328 AC: 5AN: 152310Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74488
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 22, 2022 | This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 176 of the FBXL4 protein (p.Trp176Arg). This variant is present in population databases (rs201149065, 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: 437589). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 09, 2021 | Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge - |
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.526T>C (NP_036292.2:p.Trp176Arg) [GRCH38: NC_000006.12:g.98917706A>G] 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. Based on this evidence code ClinGen Pathogenicity Calculator (PMID:28081714) suggested that the variant is Uncertain Significance - Insufficient Evidence. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at