dbSNP rs1390777006: FBXO46:p.Arg599Leu (chr19-45711700-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001080469.2(FBXO46):c.1796G>T(p.Arg599Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000725 in 1,379,240 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R599Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

FBXO46
NM_001080469.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.84

Publications

0 publications found

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]

FBXO46 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2260519).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080469.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FBXO46	NM_001080469.2	MANE Select	c.1796G>T	p.Arg599Leu	missense	Exon 2 of 2	NP_001073938.1	Q6PJ61
FBXO46	NM_001329632.1		c.1796G>T	p.Arg599Leu	missense	Exon 2 of 2	NP_001316561.1	Q6PJ61
FBXO46	NM_001329633.2		c.1796G>T	p.Arg599Leu	missense	Exon 2 of 2	NP_001316562.1	Q6PJ61

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FBXO46	ENST00000317683.4	TSL:2 MANE Select	c.1796G>T	p.Arg599Leu	missense	Exon 2 of 2	ENSP00000410007.1	Q6PJ61
FBXO46	ENST00000925224.1		c.1796G>T	p.Arg599Leu	missense	Exon 2 of 2	ENSP00000595283.1
FBXO46	ENST00000925225.1		c.1796G>T	p.Arg599Leu	missense	Exon 2 of 2	ENSP00000595284.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000730

AC:

AN:

136916

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000183

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.25e-7

AC:

AN:

1379240

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

679894

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

31428

American (AMR)

AF:

0.00

AC:

AN:

35414

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25022

East Asian (EAS)

AF:

0.00

AC:

AN:

35626

South Asian (SAS)

AF:

0.00

AC:

AN:

79088

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34762

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5650

European-Non Finnish (NFE)

AF:

9.30e-7

AC:

AN:

1074696

Other (OTH)

AF:

0.00

AC:

AN:

57554

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Benign

-0.0094

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.059

Eigen

Benign

0.038

Eigen_PC

Benign

0.0057

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.56

M_CAP

Benign

0.032

MetaRNN

Benign

0.23

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

PhyloP100

2.8

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-2.2

REVEL

Benign

0.10

Sift

Uncertain

0.012

Sift4G

Benign

0.10

Polyphen

1.0

Vest4

0.34

MutPred

0.28

Loss of methylation at R599 (P = 0.0095)

MVP

0.10

MPC

0.81

ClinPred

0.93

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.15

gMVP

0.69

Mutation Taster

=94/6

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over