Genetic Variant FBXO46:p.Pro420Leu (chr19-45712237-G-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.1259C>T(p.Pro420Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,452,382 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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. P420Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

FBXO46
NM_001080469.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.45

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:

Genome browser will be placed here

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=0.14780533).

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.1259C>T	p.Pro420Leu	missense	Exon 2 of 2	NP_001073938.1	Q6PJ61
FBXO46	NM_001329632.1		c.1259C>T	p.Pro420Leu	missense	Exon 2 of 2	NP_001316561.1	Q6PJ61
FBXO46	NM_001329633.2		c.1259C>T	p.Pro420Leu	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.1259C>T	p.Pro420Leu	missense	Exon 2 of 2	ENSP00000410007.1	Q6PJ61
FBXO46	ENST00000925224.1		c.1259C>T	p.Pro420Leu	missense	Exon 2 of 2	ENSP00000595283.1
FBXO46	ENST00000925225.1		c.1259C>T	p.Pro420Leu	missense	Exon 2 of 2	ENSP00000595284.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.89e-7

AC:

AN:

1452382

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

722540

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33324

American (AMR)

AF:

0.00

AC:

AN:

44342

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25982

East Asian (EAS)

AF:

0.00

AC:

AN:

39574

South Asian (SAS)

AF:

0.00

AC:

AN:

86074

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47182

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5730

European-Non Finnish (NFE)

AF:

9.01e-7

AC:

AN:

1110042

Other (OTH)

AF:

0.00

AC:

AN:

60132

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.021

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.43

LIST_S2

Benign

0.74

M_CAP

Benign

0.0082

MetaRNN

Benign

0.15

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.34

PhyloP100

2.4

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-0.25

REVEL

Benign

0.16

Sift

Benign

0.24

Sift4G

Benign

0.25

Polyphen

0.98

Vest4

0.25

MutPred

0.28

Gain of stability (P = 0.0106)

MVP

0.043

MPC

0.75

ClinPred

0.14

GERP RS

1.7

Varity_R

0.038

gMVP

0.32

Mutation Taster

=89/11

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over