4-15625532-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_012161.4(FBXL5):​c.1570G>A​(p.Asp524Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000539 in 1,614,002 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000056 ( 0 hom. )

Consequence

FBXL5
NM_012161.4 missense

Scores

1
6
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.76
Variant links:
Genes affected
FBXL5 (HGNC:13602): (F-box and leucine rich repeat protein 5) This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbls class and, in addition to an F-box, contains several tandem leucine-rich repeats. Alternatively spliced transcript variants have been described for this locus. [provided by RefSeq, Aug 2010]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.20774424).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FBXL5NM_012161.4 linkc.1570G>A p.Asp524Asn missense_variant Exon 9 of 11 ENST00000341285.8 NP_036293.1 Q9UKA1-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FBXL5ENST00000341285.8 linkc.1570G>A p.Asp524Asn missense_variant Exon 9 of 11 1 NM_012161.4 ENSP00000344866.3 Q9UKA1-1

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152202
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000239
AC:
6
AN:
250782
Hom.:
0
AF XY:
0.00000737
AC XY:
1
AN XY:
135604
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
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:
0.0000442
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000561
AC:
82
AN:
1461800
Hom.:
0
Cov.:
32
AF XY:
0.0000564
AC XY:
41
AN XY:
727192
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000683
Gnomad4 OTH exome
AF:
0.0000828
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152202
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74358
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000658
Hom.:
0
Bravo
AF:
0.0000227
ExAC
AF:
0.0000247
AC:
3
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jan 15, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1570G>A (p.D524N) alteration is located in exon 9 (coding exon 9) of the FBXL5 gene. This alteration results from a G to A substitution at nucleotide position 1570, causing the aspartic acid (D) at amino acid position 524 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.098
BayesDel_addAF
Benign
-0.30
T
BayesDel_noAF
Benign
-0.54
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.047
T;.
Eigen
Uncertain
0.30
Eigen_PC
Uncertain
0.42
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.94
D;D
M_CAP
Benign
0.012
T
MetaRNN
Benign
0.21
T;T
MetaSVM
Benign
-0.88
T
MutationAssessor
Uncertain
2.1
M;.
PrimateAI
Uncertain
0.61
T
PROVEAN
Benign
0.11
N;N
REVEL
Benign
0.13
Sift
Benign
0.15
T;T
Sift4G
Benign
0.55
T;T
Polyphen
0.96
D;D
Vest4
0.50
MutPred
0.45
Loss of ubiquitination at K523 (P = 0.0613);.;
MVP
0.32
MPC
0.25
ClinPred
0.27
T
GERP RS
5.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.056
gMVP
0.66

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

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: rs777161956; hg19: chr4-15627155; API