19-45711700-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001080469.2(FBXO46):​c.1796G>A​(p.Arg599Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000588 in 1,531,300 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000036 ( 0 hom. )

Consequence

FBXO46
NM_001080469.2 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.84
Variant links:
Genes affected
FBXO46 (HGNC:25069): (F-box protein 46) Members of the F-box protein family, such as FBXO46, are characterized by an approximately 40-amino acid F-box motif. SCF complexes, formed by SKP1 (MIM 601434), cullin (see CUL1; MIM 603134), and F-box proteins, act as protein-ubiquitin ligases. F-box proteins interact with SKP1 through the F box, and they interact with ubiquitination targets through other protein interaction domains (Jin et al., 2004 [PubMed 15520277]).[supplied by OMIM, Mar 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.17643285).
BS2
High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FBXO46NM_001080469.2 linkc.1796G>A p.Arg599Gln missense_variant Exon 2 of 2 ENST00000317683.4 NP_001073938.1 Q6PJ61

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FBXO46ENST00000317683.4 linkc.1796G>A p.Arg599Gln missense_variant Exon 2 of 2 2 NM_001080469.2 ENSP00000410007.1 Q6PJ61

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152060
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000730
AC:
1
AN:
136916
Hom.:
0
AF XY:
0.0000135
AC XY:
1
AN XY:
74318
show subpopulations
Gnomad AFR exome
AF:
0.000148
Gnomad AMR exome
AF:
0.00
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000363
AC:
5
AN:
1379240
Hom.:
0
Cov.:
32
AF XY:
0.00000588
AC XY:
4
AN XY:
679894
show subpopulations
Gnomad4 AFR exome
AF:
0.0000955
Gnomad4 AMR exome
AF:
0.00
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:
9.30e-7
Gnomad4 OTH exome
AF:
0.0000174
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152060
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74268
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000189

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Feb 10, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1796G>A (p.R599Q) alteration is located in exon 2 (coding exon 1) of the FBXO46 gene. This alteration results from a G to A substitution at nucleotide position 1796, causing the arginine (R) at amino acid position 599 to be replaced by a glutamine (Q). 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
0.27
BayesDel_addAF
Benign
-0.25
T
BayesDel_noAF
Benign
-0.34
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.029
T
Eigen
Benign
0.031
Eigen_PC
Benign
0.00066
FATHMM_MKL
Benign
0.50
N
LIST_S2
Benign
0.62
T
M_CAP
Benign
0.030
D
MetaRNN
Benign
0.18
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.1
L
PrimateAI
Uncertain
0.59
T
PROVEAN
Benign
-0.52
N
REVEL
Benign
0.074
Sift
Uncertain
0.029
D
Sift4G
Benign
0.23
T
Polyphen
1.0
D
Vest4
0.19
MutPred
0.19
Loss of methylation at R599 (P = 0.0095);
MVP
0.16
MPC
0.75
ClinPred
0.16
T
GERP RS
3.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.075
gMVP
0.63

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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: rs1390777006; hg19: chr19-46214958; API