NM_001278716.2:c.1067delG
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001278716.2(FBXL4):c.1067delG(p.Gly356AlafsTer15) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
FBXL4
NM_001278716.2 frameshift
NM_001278716.2 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.57
Publications
2 publications found
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]
FBXL4 Gene-Disease associations (from GenCC):
- Leigh syndromeInheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
- mitochondrial DNA depletion syndrome 13Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 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 6-98905461-GC-G is Pathogenic according to our data. Variant chr6-98905461-GC-G is described in ClinVar as Pathogenic. ClinVar VariationId is 437498.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_001278716.2. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| FBXL4 | NM_001278716.2 | MANE Select | c.1067delG | p.Gly356AlafsTer15 | frameshift | Exon 6 of 10 | NP_001265645.1 | ||
| FBXL4 | NM_012160.5 | c.1067delG | p.Gly356AlafsTer15 | frameshift | Exon 5 of 9 | NP_036292.2 | |||
| FBXL4 | NR_103836.2 | n.1052delG | non_coding_transcript_exon | Exon 4 of 8 |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| FBXL4 | ENST00000369244.7 | TSL:1 MANE Select | c.1067delG | p.Gly356AlafsTer15 | frameshift | Exon 6 of 10 | ENSP00000358247.1 | ||
| FBXL4 | ENST00000229971.2 | TSL:1 | c.1067delG | p.Gly356AlafsTer15 | frameshift | Exon 5 of 9 | ENSP00000229971.1 | ||
| FBXL4 | ENST00000892543.1 | c.1088delG | p.Gly363AlafsTer15 | frameshift | Exon 6 of 10 | ENSP00000562602.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.84e-7 AC: 1AN: 1461760Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 727174 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
AC:
1
AN:
1461760
Hom.:
Cov.:
33
AF XY:
AC XY:
0
AN XY:
727174
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
0
AN:
33470
American (AMR)
AF:
AC:
0
AN:
44716
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26126
East Asian (EAS)
AF:
AC:
0
AN:
39690
South Asian (SAS)
AF:
AC:
0
AN:
86256
European-Finnish (FIN)
AF:
AC:
0
AN:
53418
Middle Eastern (MID)
AF:
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
AC:
1
AN:
1111926
Other (OTH)
AF:
AC:
0
AN:
60392
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.375
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
ClinVar submissions as Germline
View on ClinVar Significance:Pathogenic
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
4
-
-
Mitochondrial DNA depletion syndrome 13 (4)
3
-
-
not provided (3)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
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
Publications
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