19-45712052-C-T

Variant names:

• chr19-45712052-C-T
• NM_001080469.2:c.1444G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001080469.2(FBXO46):​c.1444G>A​(p.Val482Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBXO46 NM_001080469.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.04
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXO46	NM_001080469.2	MANE Select	c.1444G>A	p.Val482Ile	missense	Exon 2 of 2	NP_001073938.1	Q6PJ61
	FBXO46	NM_001329632.1		c.1444G>A	p.Val482Ile	missense	Exon 2 of 2	NP_001316561.1	Q6PJ61
	FBXO46	NM_001329633.2		c.1444G>A	p.Val482Ile	missense	Exon 2 of 2	NP_001316562.1	Q6PJ61

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXO46	ENST00000317683.4	TSL:2 MANE Select	c.1444G>A	p.Val482Ile	missense	Exon 2 of 2	ENSP00000410007.1	Q6PJ61
	FBXO46	ENST00000925224.1		c.1444G>A	p.Val482Ile	missense	Exon 2 of 2	ENSP00000595283.1
	FBXO46	ENST00000925225.1		c.1444G>A	p.Val482Ile	missense	Exon 2 of 2	ENSP00000595284.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.56	D
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.9	L
PhyloP100		6.0
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.55	N
REVEL	Benign	0.17
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.038	D
Polyphen		0.99	D
Vest4		0.48
MutPred		0.67		Loss of sheet (P = 0.0315)
MVP		0.27
MPC		0.99
ClinPred		0.87	D
GERP RS		4.1
Varity_R		0.12
gMVP		0.95
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

hg19: chr19-46215310;