Genetic Variant FBXO42:p.Gly554Arg (chr1-16251164-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_018994.3(FBXO42):c.1660G>C(p.Gly554Arg) 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. 13/22 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

FBXO42
NM_018994.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.975

Variant links:

Genes affected

FBXO42 (HGNC:29249): (F-box protein 42) Members of the F-box protein family, such as FBXO42, are characterized by an approximately 40-amino acid F-box motif. SCF complexes, formed by SKP1 (SKP1A; 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, Dec 2010]

FBXO42 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.175872).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXO42	NM_018994.3 link	c.1660G>C	p.Gly554Arg	missense_variant	Exon 10 of 10	ENST00000375592.8	NP_061867.1	Q6P3S6
FBXO42	XM_047422747.1 link	c.1660G>C	p.Gly554Arg	missense_variant	Exon 12 of 12		XP_047278703.1
FBXO42	XM_047422750.1 link	c.1660G>C	p.Gly554Arg	missense_variant	Exon 12 of 12		XP_047278706.1
FBXO42	XM_047422751.1 link	c.1660G>C	p.Gly554Arg	missense_variant	Exon 12 of 12		XP_047278707.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FBXO42	ENST00000375592.8 link	c.1660G>C	p.Gly554Arg	missense_variant	Exon 10 of 10	1	NM_018994.3	ENSP00000364742.3	Q6P3S6
FBXO42	ENST00000444116.1 link	c.814G>C	p.Gly272Arg	missense_variant	Exon 4 of 4	5		ENSP00000412416.1	X6RKU3
FBXO42	ENST00000456164.5 link	c.814G>C	p.Gly272Arg	missense_variant	Exon 3 of 3	2		ENSP00000415663.1	X6RKU3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000399

AC:

AN:

250778

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 06, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1660G>C (p.G554R) alteration is located in exon 10 (coding exon 9) of the FBXO42 gene. This alteration results from a G to C substitution at nucleotide position 1660, causing the glycine (G) at amino acid position 554 to be replaced by an arginine (R). 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

Uncertain

0.53

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.017

T;T;T

Eigen

Benign

0.047

Eigen_PC

Benign

0.051

FATHMM_MKL

Uncertain

0.79

LIST_S2

Uncertain

0.93

D;.;D

M_CAP

Benign

0.019

MetaRNN

Benign

0.18

T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.81

L;.;.

PhyloP100

0.97

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-1.2

N;N;N

REVEL

Benign

0.12

Sift

Uncertain

0.0010

D;D;D

Sift4G

Uncertain

0.021

D;.;.

Polyphen

0.98

D;.;.

Vest4

0.12

MutPred

0.42

Loss of sheet (P = 0.0104);.;.;

MVP

0.26

MPC

0.37

ClinPred

0.43

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.2

Varity_R

0.22

gMVP

0.67

Mutation Taster

=80/20

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over