19-45711700-C-T

Variant names:

• chr19-45711700-C-T
• rs1390777006
• NM_001080469.2:c.1796G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001080469.2(FBXO46):​c.1796G>A​(p.Arg599Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000588 in 1,531,300 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: FBXO46 NM_001080469.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.84
• 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.17643285).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

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.1796G>A	p.Arg599Gln	missense	Exon 2 of 2	NP_001073938.1	Q6PJ61
	FBXO46	NM_001329632.1		c.1796G>A	p.Arg599Gln	missense	Exon 2 of 2	NP_001316561.1	Q6PJ61
	FBXO46	NM_001329633.2		c.1796G>A	p.Arg599Gln	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.1796G>A	p.Arg599Gln	missense	Exon 2 of 2	ENSP00000410007.1	Q6PJ61
	FBXO46	ENST00000925224.1		c.1796G>A	p.Arg599Gln	missense	Exon 2 of 2	ENSP00000595283.1
	FBXO46	ENST00000925225.1		c.1796G>A	p.Arg599Gln	missense	Exon 2 of 2	ENSP00000595284.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152060 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000730 AC: 1 AN: 136916 AF XY: 0.0000135

Gnomad AFR exome AF: 0.000148

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000363 AC: 5 AN: 1379240 Hom.: 0 Cov.: 32 AF XY: 0.00000588 AC XY: 4 AN XY: 679894

African (AFR) AF: 0.0000955 AC: 3 AN: 31428

American (AMR) AF: 0.00 AC: 0 AN: 35414

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25022

East Asian (EAS) AF: 0.00 AC: 0 AN: 35626

South Asian (SAS) AF: 0.00 AC: 0 AN: 79088

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34762

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5650

European-Non Finnish (NFE) AF: 9.30e-7 AC: 1 AN: 1074696

Other (OTH) AF: 0.0000174 AC: 1 AN: 57554

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152060 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74268

African (AFR) AF: 0.0000483 AC: 2 AN: 41428

American (AMR) AF: 0.0000654 AC: 1 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5124

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67988

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

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	0.27
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.029	T
Eigen	Benign	0.031
Eigen_PC	Benign	0.00066
FATHMM_MKL	Benign	0.50	N
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		2.8
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.074
Sift	Uncertain	0.029	D
Sift4G	Benign	0.23	T
Polyphen		1.0	D
Vest4		0.19
MutPred		0.19		Loss of methylation at R599 (P = 0.0095)
MVP		0.16
MPC		0.75
ClinPred		0.16	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.075
gMVP		0.63
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

dbSNP: rs1390777006; hg19: chr19-46214958;