rs143154211
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1
The NM_001278716.2(FBXL4):c.737T>C(p.Ile246Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000884 in 1,614,062 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I246V) has been classified as Uncertain significance.
Frequency
Consequence
NM_001278716.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FBXL4 | NM_001278716.2 | c.737T>C | p.Ile246Thr | missense_variant | 5/10 | ENST00000369244.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBXL4 | ENST00000369244.7 | c.737T>C | p.Ile246Thr | missense_variant | 5/10 | 1 | NM_001278716.2 | P1 | |
FBXL4 | ENST00000229971.2 | c.737T>C | p.Ile246Thr | missense_variant | 4/9 | 1 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000723 AC: 110AN: 152204Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000649 AC: 163AN: 251308Hom.: 0 AF XY: 0.000663 AC XY: 90AN XY: 135818
GnomAD4 exome AF: 0.000901 AC: 1317AN: 1461742Hom.: 1 Cov.: 31 AF XY: 0.000902 AC XY: 656AN XY: 727172
GnomAD4 genome ? AF: 0.000722 AC: 110AN: 152320Hom.: 0 Cov.: 32 AF XY: 0.000685 AC XY: 51AN XY: 74484
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:2
Uncertain significance, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Feb 29, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2023 | FBXL4: BP4 - |
Mitochondrial DNA depletion syndrome 13 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | May 03, 2019 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
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.737T>C (NP_036292.2:p.Ile246Thr) [GRCH38: NC_000006.12:g.98917495A>G] 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. Based on this evidence code ClinGen Pathogenicity Calculator (PMID:28081714) suggested that the variant is Uncertain Significance - Conflicting Evidence. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at