6-98899282-G-A
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001278716.2(FBXL4):c.1303C>T(p.Arg435Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000242 in 1,613,652 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. R435R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000025 ( 0 hom. )
Consequence
FBXL4
NM_001278716.2 stop_gained
NM_001278716.2 stop_gained
Scores
3
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1
Clinical Significance
Conservation
PhyloP100: 5.50
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 Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 6-98899282-G-A is Pathogenic according to our data. Variant chr6-98899282-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 66091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-98899282-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| FBXL4 | NM_001278716.2 | c.1303C>T | p.Arg435Ter | stop_gained | 7/10 | ENST00000369244.7 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| FBXL4 | ENST00000369244.7 | c.1303C>T | p.Arg435Ter | stop_gained | 7/10 | 1 | NM_001278716.2 | P1 | |
| FBXL4 | ENST00000229971.2 | c.1303C>T | p.Arg435Ter | stop_gained | 6/9 | 1 | P1 |
Frequencies
GnomAD3 genomes 0.0000197 AC: 3AN: 152144Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000398 AC: 10AN: 250950Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135608
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GnomAD4 exome AF: 0.0000246 AC: 36AN: 1461508Hom.: 0 Cov.: 33 AF XY: 0.0000261 AC XY: 19AN XY: 727054
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GnomAD4 genome 0.0000197 AC: 3AN: 152144Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74302
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Mitochondrial DNA depletion syndrome 13 Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 31, 2022 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 05, 2013 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jun 24, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with mitochondrial DNA depletion syndrome 13 (encephalomyopathic type) (MIM#615471). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Affected individuals carrying the same variant have been reported to display clinical variability (PMID: 30804983). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (10 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic in multiple individuals (ClinVar, PMID: 30771478). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
| 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.1303C>T (NP_036292.2:p.Arg435Ter) [GRCH38: NC_000006.12:g.98899282G>A] variant in FBXL4 gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:23993193 ; 27099744 . This variant meets one or more of the following evidence codes reported in the ACMG-guideline. PVS1:This variant is a predcted null variant in FBXL4 where loss of function is a known mechanism of disease. 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. 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 Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Sep 01, 2022 | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). This stop-gained (nonsense) variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000066091/ PMID: 23993193). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 03, 2014 | The c.1303C>T (p.R435*) alteration, located in exon 6 (coding exon 4) of the FBXL4 gene, consists of a C to T substitution at nucleotide position 1303. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 435. Premature stop codons are typically deleterious in nature (Richards, 2015). The heterozygous missense change is ultra rare in healthy individuals:_x000D_ Based on data from the NHLBI Exome Sequencing Project (ESP), the FBXL4 c.1303C>T alteration was observed in 1 among 13006 total alleles studied (0.01%). Allele frequency data for this nucleotide position are not currently available from the 1000 Genomes Project. This variant is reported in the SNPDatabase as rs201889294. Based on the available evidence, this alteration is classified as pathogenic. - |
Mitochondrial DNA depletion syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 23, 2016 | The p.Arg435X (NM_012160.4 c.1303C>T) variant in FBXL4 has been reported in 1 ho mozygous and 2 compound heterozygous individuals with clinical features of mitoc hondrial DNA depletion syndrome 13 (Bonnen 2013, Van Rij 2016, and Prionska 2016 ). This variant has been identified in 0.012% (1/8652) of East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSN P rs201889294). This nonsense variant leads to a premature termination codon at position 435, which is predicted to lead to a truncated or absent protein. In su mmary, the p.Arg435X variant meets criteria to be classified as pathogenic for m itochondrial DNA depletion syndrome in an autosomal recessive manner, based upon occurrence in patients and predicted functional impact. - |
not provided Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 22, 2023 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 23993193, 27290639, 30804983, 30609409, 30771478, 30369941, 27099744) - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A
Vest4
GERP RS
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