19-45712246-T-G

Variant names:

• chr19-45712246-T-G
• NM_001080469.2:c.1250A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001080469.2(FBXO46):​c.1250A>C​(p.Asp417Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. 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: 0.258
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.047837496).

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.1250A>C	p.Asp417Ala	missense	Exon 2 of 2	NP_001073938.1	Q6PJ61
	FBXO46	NM_001329632.1		c.1250A>C	p.Asp417Ala	missense	Exon 2 of 2	NP_001316561.1	Q6PJ61
	FBXO46	NM_001329633.2		c.1250A>C	p.Asp417Ala	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.1250A>C	p.Asp417Ala	missense	Exon 2 of 2	ENSP00000410007.1	Q6PJ61
	FBXO46	ENST00000925224.1		c.1250A>C	p.Asp417Ala	missense	Exon 2 of 2	ENSP00000595283.1
	FBXO46	ENST00000925225.1		c.1250A>C	p.Asp417Ala	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	0.070
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	15
DANN	Benign	0.40
DEOGEN2	Benign	0.015	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.048	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.55	N
PhyloP100		0.26
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.085
Sift	Benign	0.65	T
Sift4G	Benign	0.72	T
Polyphen		0.013	B
Vest4		0.14
MutPred		0.19		Gain of catalytic residue at D417 (P = 0.0099)
MVP		0.043
MPC		0.82
ClinPred		0.055	T
GERP RS		3.1
Varity_R		0.076
gMVP		0.27
Mutation Taster		=86/14	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: chr19-46215504;