rs754532558
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2
The NM_001278716.2(FBXL4):c.3G>A(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000124 in 1,611,504 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 (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Consequence
FBXL4
NM_001278716.2 start_lost
NM_001278716.2 start_lost
Scores
4
4
7
Clinical Significance
Conservation
PhyloP100: 6.16
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PVS1
?
Start lost variant, no new inframe start found.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FBXL4 | NM_001278716.2 | c.3G>A | p.Met1? | start_lost | 4/10 | ENST00000369244.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBXL4 | ENST00000369244.7 | c.3G>A | p.Met1? | start_lost | 4/10 | 1 | NM_001278716.2 | P1 | |
FBXL4 | ENST00000229971.2 | c.3G>A | p.Met1? | start_lost | 3/9 | 1 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152134Hom.: 0 Cov.: 33
GnomAD3 genomes
?
AF:
AC:
1
AN:
152134
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.00000400 AC: 1AN: 250114Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135340
GnomAD3 exomes
AF:
AC:
1
AN:
250114
Hom.:
AF XY:
AC XY:
1
AN XY:
135340
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1459252Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 725514
GnomAD4 exome
AF:
AC:
1
AN:
1459252
Hom.:
Cov.:
32
AF XY:
AC XY:
1
AN XY:
725514
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152252Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74438
GnomAD4 genome
?
AF:
AC:
1
AN:
152252
Hom.:
Cov.:
33
AF XY:
AC XY:
1
AN XY:
74438
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
ExAC
?
AF:
AC:
1
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Mitochondrial DNA depletion syndrome 13 Uncertain:1
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.3G>A () [GRCH38: NC_000006.12:g.98926986C>T] 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. Based on this evidence code ClinGen Pathogenicity Calculator (PMID:28081714) suggested that the variant is Uncertain Significance - Insufficient Evidence. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D
MetaSVM
Benign
T
MutationTaster
Benign
D;D
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift
Pathogenic
D;D
Sift4G
Benign
T;T
Polyphen
B;B
Vest4
MutPred
Gain of catalytic residue at M1 (P = 0.0178);Gain of catalytic residue at M1 (P = 0.0178);
MVP
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at