rs754142863

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_ModeratePP5_Moderate

The NM_001278716.2(FBXL4):​c.1304G>T​(p.Arg435Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,424 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R435Q) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

FBXL4
NM_001278716.2 missense

Scores

8
8
3

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.57
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 Pathogenic. Variant got 10 ACMG points.

PM1
In a repeat LRR 3 (size 21) in uniprot entity FBXL4_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_001278716.2
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr6-98899281-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 430470.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Pathogenic=1, Uncertain_significance=1}.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.906
PP5
Variant 6-98899281-C-A is Pathogenic according to our data. Variant chr6-98899281-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 437476.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-98899281-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
FBXL4NM_001278716.2 linkuse as main transcriptc.1304G>T p.Arg435Leu missense_variant 7/10 ENST00000369244.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
FBXL4ENST00000369244.7 linkuse as main transcriptc.1304G>T p.Arg435Leu missense_variant 7/101 NM_001278716.2 P1
FBXL4ENST00000229971.2 linkuse as main transcriptc.1304G>T p.Arg435Leu missense_variant 6/91 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461424
Hom.:
0
Cov.:
33
AF XY:
0.00000138
AC XY:
1
AN XY:
727006
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Mitochondrial DNA depletion syndrome 13 Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingWong Mito Lab, Molecular and Human Genetics, Baylor College of MedicineAug 10, 2017The NM_012160.4:c.1304G>T (NP_036292.2:p.Arg435Leu) [GRCH38: NC_000006.12:g.98899281C>A] variant in FBXL4 gene is interpretated to be a Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:25868664 . 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. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.23
D
BayesDel_noAF
Uncertain
0.10
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Benign
0.29
T;T
Eigen
Pathogenic
0.70
Eigen_PC
Pathogenic
0.69
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
.;D
M_CAP
Uncertain
0.10
D
MetaRNN
Pathogenic
0.91
D;D
MetaSVM
Benign
-1.0
T
MutationAssessor
Uncertain
2.8
M;M
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.64
T
PROVEAN
Pathogenic
-5.3
D;D
REVEL
Uncertain
0.56
Sift
Uncertain
0.0020
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
0.99
D;D
Vest4
0.93
MutPred
0.76
Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);
MVP
0.54
MPC
0.43
ClinPred
1.0
D
GERP RS
5.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.68
gMVP
0.81

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.21
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.21
Position offset: -13

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: rs754142863; hg19: chr6-99347157; API