rs375383163

Variant names:

• chr19-45712886-C-G
• rs375383163
• NM_001080469.2:c.610G>C

Your query was ambiguous. Multiple possible variants found:

• chr19-45712886-C-G
• chr19-45712886-C-T
• chr19-45712886-C-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.610G>C​(p.Ala204Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A204T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: FBXO46 NM_001080469.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.52
• Publications: 3 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=0.18623781).
• BS2: High AC in GnomAdExome4 at 14 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.610G>C	p.Ala204Pro	missense	Exon 2 of 2	NP_001073938.1	Q6PJ61
	FBXO46	NM_001329632.1		c.610G>C	p.Ala204Pro	missense	Exon 2 of 2	NP_001316561.1	Q6PJ61
	FBXO46	NM_001329633.2		c.610G>C	p.Ala204Pro	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.610G>C	p.Ala204Pro	missense	Exon 2 of 2	ENSP00000410007.1	Q6PJ61
	FBXO46	ENST00000925224.1		c.610G>C	p.Ala204Pro	missense	Exon 2 of 2	ENSP00000595283.1
	FBXO46	ENST00000925225.1		c.610G>C	p.Ala204Pro	missense	Exon 2 of 2	ENSP00000595284.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461050 Hom.: 0 Cov.: 36 AF XY: 0.00000688 AC XY: 5 AN XY: 726846

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.0000448 AC: 2 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26086

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86202

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53174

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000900 AC: 10 AN: 1111674

Other (OTH) AF: 0.0000166 AC: 1 AN: 60328

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000225 Hom.: 0

Bravo AF: 0.0000491

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	0.10
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.020	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L
PhyloP100		1.5
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	0.020	N
REVEL	Benign	0.23
Sift	Benign	0.054	T
Sift4G	Benign	0.17	T
Polyphen		0.99	D
Vest4		0.34
MutPred		0.18		Gain of loop (P = 0.0435)
MVP		0.21
MPC		1.9
ClinPred		0.31	T
GERP RS		4.4
Varity_R		0.11
gMVP		0.20
Mutation Taster		=78/22	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: rs375383163; hg19: chr19-46216144;