19-45712886-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001080469.2(FBXO46):​c.610G>A​(p.Ala204Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000626 in 1,613,242 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A204P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000066 ( 0 hom. )

Consequence

FBXO46
NM_001080469.2 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.52
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 Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.028689533).
BS2
High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FBXO46NM_001080469.2 linkc.610G>A p.Ala204Thr 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.610G>A p.Ala204Thr missense_variant Exon 2 of 2 2 NM_001080469.2 ENSP00000410007.1 Q6PJ61
FBXO46ENST00000586899.1 linkc.*58G>A downstream_gene_variant 3 ENSP00000468336.1 K7ERN4

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152192
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.000864
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000155
AC:
38
AN:
245140
Hom.:
0
AF XY:
0.000194
AC XY:
26
AN XY:
133680
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00111
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000524
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000999
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000657
AC:
96
AN:
1461050
Hom.:
0
Cov.:
36
AF XY:
0.0000825
AC XY:
60
AN XY:
726846
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.000997
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000441
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000180
Gnomad4 OTH exome
AF:
0.000199
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152192
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74342
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.000864
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000414
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000450
Hom.:
0
Bravo
AF:
0.0000567
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000121
AC:
1
ExAC
AF:
0.000157
AC:
19
EpiCase
AF:
0.000164
EpiControl
AF:
0.000237

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Sep 22, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.610G>A (p.A204T) 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 610, causing the alanine (A) at amino acid position 204 to be replaced by a threonine (T). 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
0.070
BayesDel_addAF
Benign
-0.36
T
BayesDel_noAF
Benign
-0.41
CADD
Benign
17
DANN
Benign
0.61
DEOGEN2
Benign
0.022
T
Eigen
Benign
-0.49
Eigen_PC
Benign
-0.53
FATHMM_MKL
Benign
0.14
N
LIST_S2
Benign
0.70
T
M_CAP
Benign
0.015
T
MetaRNN
Benign
0.029
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.34
N
PrimateAI
Uncertain
0.78
T
PROVEAN
Benign
-0.10
N
REVEL
Benign
0.080
Sift
Benign
0.31
T
Sift4G
Benign
0.45
T
Polyphen
0.95
P
Vest4
0.088
MVP
0.21
MPC
1.6
ClinPred
0.058
T
GERP RS
4.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.8
Varity_R
0.050
gMVP
0.13

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: rs375383163; hg19: chr19-46216144; COSMIC: COSV58349150; COSMIC: COSV58349150; API