1-16251302-G-C

Position:

• chr1-16251302-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018994.3(FBXO42):​c.1522C>G​(p.Pro508Ala) 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: FBXO42 NM_018994.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.04

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.028737575).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBXO42	NM_018994.3	c.1522C>G	p.Pro508Ala	missense_variant	10/10	ENST00000375592.8	NP_061867.1
FBXO42	XM_047422747.1	c.1522C>G	p.Pro508Ala	missense_variant	12/12		XP_047278703.1
FBXO42	XM_047422750.1	c.1522C>G	p.Pro508Ala	missense_variant	12/12		XP_047278706.1
FBXO42	XM_047422751.1	c.1522C>G	p.Pro508Ala	missense_variant	12/12		XP_047278707.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBXO42	ENST00000375592.8	c.1522C>G	p.Pro508Ala	missense_variant	10/10	1	NM_018994.3	ENSP00000364742.3
FBXO42	ENST00000444116.1	c.676C>G	p.Pro226Ala	missense_variant	4/4	5		ENSP00000412416.1
FBXO42	ENST00000456164.5	c.676C>G	p.Pro226Ala	missense_variant	3/3	2		ENSP00000415663.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251462 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135904

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS 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.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 08, 2024

The c.1522C>G (p.P508A) alteration is located in exon 10 (coding exon 9) of the FBXO42 gene. This alteration results from a C to G substitution at nucleotide position 1522, causing the proline (P) at amino acid position 508 to be replaced by an alanine (A). 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	Benign	0.058
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	4.9
DANN	Benign	0.45
DEOGEN2	Benign	0.014	T;T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.0
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.62	T;.;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.029	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;.;.
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.48	N;N;N
REVEL	Benign	0.050
Sift	Benign	0.16	T;T;T
Sift4G	Benign	0.42	T;.;.
Polyphen		0.0	B;.;.
Vest4		0.096
MutPred		0.34		Gain of sheet (P = 0.0061);.;.;
MVP		0.19
MPC		0.25
ClinPred		0.024	T
GERP RS		1.5
Varity_R		0.017
gMVP		0.24

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

LitVar

Other links and lift over

dbSNP: rs775291125; hg19: chr1-16577797; COSMIC: COSV65045763;