NM_001278716.2:c.565C>T
Variant summary
Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP2PP3
The NM_001278716.2(FBXL4):c.565C>T(p.Arg189Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000731 in 1,613,146 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R189L) has been classified as Uncertain significance.
Frequency
Consequence
NM_001278716.2 missense
Scores
Clinical Significance
Conservation
Publications
- Leigh syndromeInheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
- mitochondrial DNA depletion syndrome 13Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
Genome browser will be placed here
ACMG classification
Our verdict: Uncertain_significance. The variant received 4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000395 AC: 6AN: 152084Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.0000844 AC: 21AN: 248884 AF XY: 0.0000594 show subpopulations
GnomAD4 exome AF: 0.0000767 AC: 112AN: 1461062Hom.: 0 Cov.: 31 AF XY: 0.0000702 AC XY: 51AN XY: 726774 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000395 AC: 6AN: 152084Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74282 show subpopulations
ClinVar
Submissions by phenotype
Mitochondrial DNA depletion syndrome 13 Uncertain:1
The NM_012160.4:c.565C>T (NP_036292.2:p.Arg189Cys) [GRCH38: NC_000006.12:g.98917667G>A] 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. PP3:Computational evidence/predictors indicate the variant has deleterious effect on FBXL4 structure, function, or protein-protein interaction. Based on this evidence code ClinGen Pathogenicity Calculator (PMID:28081714) suggested that the variant is Uncertain Significance - Insufficient Evidence. -
not provided Uncertain:1
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 189 of the FBXL4 protein (p.Arg189Cys). This variant is present in population databases (rs373308410, gnomAD 0.02%). 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: 437599). 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