chr3-196584190-C-T

Variant names:

• chr3-196584190-C-T
• NM_001105573.2:c.733C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001105573.2(FBXO45):​c.733C>T​(p.Arg245Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,612 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FBXO45 NM_001105573.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.92

Genes affected

FBXO45 (HGNC:29148): (F-box protein 45) Members of the F-box protein family, such as FBXO45, 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 (summary by Jin et al., 2004 [PubMed 15520277]).[supplied by OMIM, Jan 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXO45	NM_001105573.2	c.733C>T	p.Arg245Cys	missense_variant	Exon 3 of 3	ENST00000311630.7	NP_001099043.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBXO45	ENST00000311630.7	c.733C>T	p.Arg245Cys	missense_variant	Exon 3 of 3	1	NM_001105573.2	ENSP00000310332.6
FBXO45	ENST00000440469.1	c.196C>T	p.Arg66Cys	missense_variant	Exon 3 of 3	2		ENSP00000389868.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461612 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727082

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.733C>T (p.R245C) alteration is located in exon 3 (coding exon 3) of the FBXO45 gene. This alteration results from a C to T substitution at nucleotide position 733, causing the arginine (R) at amino acid position 245 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.18	T;D
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Benign	0.074	D
MetaRNN	Uncertain	0.72	D;D
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Pathogenic	2.9	.;M
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-4.7	D;D
REVEL	Uncertain	0.42
Sift	Benign	0.070	T;T
Sift4G	Uncertain	0.031	D;D
Polyphen		1.0	.;D
Vest4		0.67
MutPred		0.65		.;Gain of glycosylation at T240 (P = 0.0891);
MVP		0.88
MPC		2.6
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.41
gMVP		0.74

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-196311061;