rs201858974
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_001278716.2(FBXL4):āc.527G>Cā(p.Trp176Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000124 in 1,592,802 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. W176R) has been classified as Uncertain significance.
Frequency
Consequence
NM_001278716.2 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FBXL4 | NM_001278716.2 | c.527G>C | p.Trp176Ser | missense_variant | 5/10 | ENST00000369244.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBXL4 | ENST00000369244.7 | c.527G>C | p.Trp176Ser | missense_variant | 5/10 | 1 | NM_001278716.2 | P1 | |
FBXL4 | ENST00000229971.2 | c.527G>C | p.Trp176Ser | missense_variant | 4/9 | 1 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000145 AC: 22AN: 151830Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000208 AC: 48AN: 230400Hom.: 0 AF XY: 0.000232 AC XY: 29AN XY: 124738
GnomAD4 exome AF: 0.000121 AC: 175AN: 1440846Hom.: 0 Cov.: 31 AF XY: 0.000128 AC XY: 92AN XY: 716122
GnomAD4 genome ? AF: 0.000145 AC: 22AN: 151956Hom.: 0 Cov.: 32 AF XY: 0.000162 AC XY: 12AN XY: 74278
ClinVar
Submissions by phenotype
Mitochondrial DNA depletion syndrome 13 Uncertain:2
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.527G>C (NP_036292.2:p.Trp176Ser) [GRCH38: NC_000006.12:g.98917705C>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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 24, 2021 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 09, 2022 | This sequence change replaces tryptophan, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 176 of the FBXL4 protein (p.Trp176Ser). This variant is present in population databases (rs201858974, gnomAD 0.1%). 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: 437590). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at