8-144355593-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_012162.4(FBXL6):c.1558C>T(p.Arg520Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000199 in 1,611,284 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 0.000026 ( 0 hom., cov: 30)
Exomes 𝑓: 0.000019 ( 0 hom. )
Consequence
FBXL6
NM_012162.4 missense
NM_012162.4 missense
Scores
1
7
8
Clinical Significance
Conservation
PhyloP100: 0.873
Genes affected
FBXL6 (HGNC:13603): (F-box and leucine rich repeat protein 6) This gene encodes a member of a family of proteins that are characterized by an F-box motif. The encoded protein also contains leucine-rich repeats. F-box-containing proteins comprise one of the subunits of the SCF (SKP1-cullin-F-box) complex, which functions in phosphorylation-dependent ubiquitination. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]
SLC52A2 (HGNC:30224): (solute carrier family 52 member 2) This gene encodes a membrane protein which belongs to the riboflavin transporter family. In humans, riboflavin must be obtained by intestinal absorption because it cannot be synthesized by the body. The water-soluble vitamin riboflavin is processed to the coenzymes flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) which then act as intermediaries in many cellular metabolic reactions. Paralogous members of the riboflavin transporter gene family are located on chromosomes 17 and 20. Unlike other members of this family, this gene has higher expression in brain tissue than small intestine. Alternative splicing of this gene results in multiple transcript variants encoding the same protein. Mutations in this gene have been associated with Brown-Vialetto-Van Laere syndrome 2 - an autosomal recessive progressive neurologic disorder characterized by deafness, bulbar dysfunction, and axial and limb hypotonia. [provided by RefSeq, Jul 2012]
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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=0.25707144).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FBXL6 | NM_012162.4 | c.1558C>T | p.Arg520Trp | missense_variant | 9/9 | ENST00000331890.6 | |
FBXL6 | NM_024555.6 | c.1540C>T | p.Arg514Trp | missense_variant | 9/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBXL6 | ENST00000331890.6 | c.1558C>T | p.Arg520Trp | missense_variant | 9/9 | 1 | NM_012162.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152154Hom.: 0 Cov.: 30
GnomAD3 genomes
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GnomAD3 exomes AF: 0.0000241 AC: 6AN: 248796Hom.: 0 AF XY: 0.0000296 AC XY: 4AN XY: 135272
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GnomAD4 exome AF: 0.0000192 AC: 28AN: 1459012Hom.: 0 Cov.: 29 AF XY: 0.0000220 AC XY: 16AN XY: 725804
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GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152272Hom.: 0 Cov.: 30 AF XY: 0.0000269 AC XY: 2AN XY: 74452
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 16, 2021 | The c.1558C>T (p.R520W) alteration is located in exon 9 (coding exon 9) of the FBXL6 gene. This alteration results from a C to T substitution at nucleotide position 1558, causing the arginine (R) at amino acid position 520 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Pathogenic
Dann
Pathogenic
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationTaster
Benign
N;N;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D
REVEL
Benign
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Vest4
MVP
MPC
0.30
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at