rs766005419
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_000507.4(FBP1):c.472C>T(p.Arg158Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000359 in 1,613,756 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R158R) has been classified as Likely benign.
Frequency
Consequence
NM_000507.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FBP1 | NM_000507.4 | c.472C>T | p.Arg158Trp | missense_variant | 4/7 | ENST00000375326.9 | |
FBP1 | NM_001127628.2 | c.472C>T | p.Arg158Trp | missense_variant | 5/8 | ||
FBP1 | XM_006717005.5 | c.226C>T | p.Arg76Trp | missense_variant | 4/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBP1 | ENST00000375326.9 | c.472C>T | p.Arg158Trp | missense_variant | 4/7 | 1 | NM_000507.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152214Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000319 AC: 8AN: 250548Hom.: 0 AF XY: 0.0000443 AC XY: 6AN XY: 135534
GnomAD4 exome AF: 0.0000376 AC: 55AN: 1461542Hom.: 0 Cov.: 33 AF XY: 0.0000358 AC XY: 26AN XY: 727074
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152214Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74352
ClinVar
Submissions by phenotype
Fructose-biphosphatase deficiency Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 07, 2023 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 158 of the FBP1 protein (p.Arg158Trp). This variant is present in population databases (rs766005419, gnomAD 0.02%). This missense change has been observed in individual(s) with fructose-1,6-bisphosphatase deficiency (PMID: 25601412, 29203193, 29774539). ClinVar contains an entry for this variant (Variation ID: 561988). 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 FBP1 protein function. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | May 22, 2022 | Amino acid change identical to known pathogenic variant has been previously reported with established evidence (ClinVar ID: VCV000561988, PMID:25601412). This variant was previously reported in trans with another pathogenic variant in this gene (PMID: 29203193, 29774539). In silico prediction tools and conservation analysis predicted that this variant was probably damaging to the protein structure/function (REVEL: 0.775>=0.6, 3CNET: 0.869>=0.75). It has been reported with an extremely low frequency in the gnomAD v2.1.1 (https://gnomad.broadinstitute.org/) dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital | Jul 11, 2013 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Centogene AG - the Rare Disease Company | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 24, 2023 | Variant summary: FBP1 c.472C>T (p.Arg158Trp) results in a non-conservative amino acid change to a highly conserved residue (HGMD) located in the Fructose-1-6-bisphosphatase class I, N-terminal (IPR033391) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 250548 control chromosomes (gnomAD). c.472C>T has been reported in the literature in multiple individuals affected with Fructose-biphosphatase deficiency (Lebigot_2015, Bhai_2018, Cheema_2020), and at least one was reported as compound heterozygous with a truncating variant. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in a loss of enzymatic activity (Sakuma_2023). The following publications have been ascertained in the context of this evaluation (PMID: 25601412, 29774539, 33083013, 37507476). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jun 02, 2022 | PP3, PP4, PM2, PM3, PS4 - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at