rs17058965

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_001278716.2(FBXL4):ā€‹c.429A>Gā€‹(p.Leu143Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000833 in 1,614,162 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.0044 ( 5 hom., cov: 32)
Exomes š‘“: 0.00046 ( 5 hom. )

Consequence

FBXL4
NM_001278716.2 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.37
Variant links:
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 Benign. Variant got -16 ACMG points.

BP6
Variant 6-98926560-T-C is Benign according to our data. Variant chr6-98926560-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 382986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-98926560-T-C is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00438 (667/152302) while in subpopulation AFR AF= 0.0154 (640/41556). AF 95% confidence interval is 0.0144. There are 5 homozygotes in gnomad4. There are 307 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
FBXL4NM_001278716.2 linkuse as main transcriptc.429A>G p.Leu143Leu synonymous_variant 4/10 ENST00000369244.7 NP_001265645.1 Q9UKA2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FBXL4ENST00000369244.7 linkuse as main transcriptc.429A>G p.Leu143Leu synonymous_variant 4/101 NM_001278716.2 ENSP00000358247.1 Q9UKA2
FBXL4ENST00000229971.2 linkuse as main transcriptc.429A>G p.Leu143Leu synonymous_variant 3/91 ENSP00000229971.1 Q9UKA2

Frequencies

GnomAD3 genomes
AF:
0.00438
AC:
666
AN:
152184
Hom.:
5
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0154
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00118
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00383
GnomAD3 exomes
AF:
0.00119
AC:
298
AN:
251358
Hom.:
2
AF XY:
0.000861
AC XY:
117
AN XY:
135838
show subpopulations
Gnomad AFR exome
AF:
0.0165
Gnomad AMR exome
AF:
0.000694
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.000652
GnomAD4 exome
AF:
0.000463
AC:
677
AN:
1461860
Hom.:
5
Cov.:
31
AF XY:
0.000402
AC XY:
292
AN XY:
727224
show subpopulations
Gnomad4 AFR exome
AF:
0.0170
Gnomad4 AMR exome
AF:
0.000783
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000464
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000899
Gnomad4 OTH exome
AF:
0.000927
GnomAD4 genome
AF:
0.00438
AC:
667
AN:
152302
Hom.:
5
Cov.:
32
AF XY:
0.00412
AC XY:
307
AN XY:
74484
show subpopulations
Gnomad4 AFR
AF:
0.0154
Gnomad4 AMR
AF:
0.00118
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00379
Alfa
AF:
0.00216
Hom.:
0
Bravo
AF:
0.00508

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Benign, criteria provided, single submitterclinical testingGeneDxNov 22, 2019- -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 29, 2024- -
Mitochondrial DNA depletion syndrome 13 Benign:1
Likely benign, criteria provided, single submitterreference populationWong Mito Lab, Molecular and Human Genetics, Baylor College of MedicineAug 10, 2017The NM_012160.4:c.429A>G (NP_036292.2:p.Leu143=) [GRCH38: NC_000006.12:g.98926560T>C] variant in FBXL4 gene is interpretated to be a Likely Benign based on ACMG guidelines (PMID: 25741868). This variant meets one or more of the following evidence codes reported in the ACMG-guideline. BS1:The minor allele frequency of this allele is high for Mitochondrial DNA depletion syndrome 13. BP4:Computational evidence/predictors indicate no impact on the FBXL4 structure, function, or protein-protein interaction. BP5:The variant is found in a case with alternate cuase. BP7:The variant is silent with non predicted splice impact. Based on this evidence code ClinGen Pathogenicity Calculator (PMID:28081714) suggested that the variant is Likely Benign. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.56
CADD
Benign
14
DANN
Benign
0.74

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.25
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.25
Position offset: 26

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs17058965; hg19: chr6-99374436; COSMIC: COSV57747252; API