rs201989042
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3PP5
The NM_001278716.2(FBXL4):c.1790A>C(p.Gln597Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000329 in 1,613,216 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000035 ( 0 hom. )
Consequence
FBXL4
NM_001278716.2 missense
NM_001278716.2 missense
Scores
4
8
6
Clinical Significance
Conservation
PhyloP100: 7.67
Genes affected
FBXL4 (HGNC:13601): (F-box and leucine rich repeat protein 4) This gene encodes a member of the F-box protein family, which are characterized by an approximately 40 amino acid motif, the F-box. F-box proteins constitute one subunit of modular E3 ubiquitin ligase complexes, called SCF complexes, which function in phosphorylation-dependent ubiquitination. The F-box domain mediates protein-protein interactions and binds directly to S-phase kinase-associated protein 1. In addition to an F-box domain, the encoded protein contains at least 9 tandem leucine-rich repeats. The ubiquitin ligase complex containing the encoded protein may function in cell-cycle control by regulating levels of lysine-specific demethylase 4A. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM1
?
In a repeat LRR 9 (size 25) in uniprot entity FBXL4_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_001278716.2
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.831
PP5
?
Variant 6-98874354-T-G is Pathogenic according to our data. Variant chr6-98874354-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 437486.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Pathogenic=1, Uncertain_significance=1}. Variant chr6-98874354-T-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FBXL4 | NM_001278716.2 | c.1790A>C | p.Gln597Pro | missense_variant | 10/10 | ENST00000369244.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBXL4 | ENST00000369244.7 | c.1790A>C | p.Gln597Pro | missense_variant | 10/10 | 1 | NM_001278716.2 | P1 | |
FBXL4 | ENST00000229971.2 | c.1790A>C | p.Gln597Pro | missense_variant | 9/9 | 1 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152170Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000200 AC: 5AN: 250346Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135306
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GnomAD4 exome AF: 0.0000349 AC: 51AN: 1461046Hom.: 0 Cov.: 31 AF XY: 0.0000344 AC XY: 25AN XY: 726860
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152170Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74332
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Mitochondrial DNA depletion syndrome 13 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine | Aug 10, 2017 | The NM_012160.4:c.1790A>C (NP_036292.2:p.Gln597Pro) [GRCH38: NC_000006.12:g.98874354T>G] variant in FBXL4 gene is interpretated to be a Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:23993194 . 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. PM3:Detected in trans with a pathogenic variant for Mitochondrial DNA depletion syndrome 13 which is a recessive disorder. PP1:This variant is co-segregated with Mitochondrial DNA depletion syndrome 13 in multiple affected family members. PP2:This is a missense variant in FBXL4 with a low rate of benign and high rate of pathogenic missense variations. PP3:Computational evidence/predictors indicate the variant has deleterious effect on FBXL4 structure, function, or protein-protein interaction. PP4:Patient’s phenotype or family history is highly specific for FBXL4. PP5:Reputable source(s) suggest that the variant is pathogenic. Based on this evidence code ClinGen Pathogenicity Calculator (PMID:28081714) suggested that the variant is Likely Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 01, 2017 | This mutation has been previously reported as disease-causing and was found once in our laboratory in trans with another pathogenic variant in an 8-year-old female with regression, basal ganglia abnormalities, absent speech, autistic features, hypotonia, spasticity, exercise intolerance, ataxia, severe renal tubular acidosis, scoliosis, primary mitochondrial respiratory chain disease - |
not provided Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 23, 2018 | The Q597P variant has been published in patients who also harbored another variant in the FBXL4 gene with symptoms that include early-onset lactic acidemia, hypotonia, encephalopathy, hyperammonemia, defects in the respiratory chain and mitochondrial DNA depletion (Gai et al. 2013; Morton et al. 2016). The Q597P variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The Q597P variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In summary, we interpret this variant as likely pathogenic; however, the possibility that it is benign cannot be excluded. - |
Uncertain significance, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Mar 08, 2016 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Benign
T;T
Eigen
Uncertain
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
N;N
REVEL
Benign
Sift
Benign
T;T
Sift4G
Uncertain
D;D
Polyphen
D;D
Vest4
MutPred
Loss of catalytic residue at Q597 (P = 0.0297);Loss of catalytic residue at Q597 (P = 0.0297);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at