1-16251091-C-T

Variant names:

• chr1-16251091-C-T
• rs2081586387
• NM_018994.3:c.1733G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018994.3(FBXO42):​c.1733G>A​(p.Ser578Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: FBXO42 NM_018994.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.35

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

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=0.2431502).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXO42	NM_018994.3	c.1733G>A	p.Ser578Asn	missense_variant	Exon 10 of 10	ENST00000375592.8	NP_061867.1
FBXO42	XM_047422747.1	c.1733G>A	p.Ser578Asn	missense_variant	Exon 12 of 12		XP_047278703.1
FBXO42	XM_047422750.1	c.1733G>A	p.Ser578Asn	missense_variant	Exon 12 of 12		XP_047278706.1
FBXO42	XM_047422751.1	c.1733G>A	p.Ser578Asn	missense_variant	Exon 12 of 12		XP_047278707.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBXO42	ENST00000375592.8	c.1733G>A	p.Ser578Asn	missense_variant	Exon 10 of 10	1	NM_018994.3	ENSP00000364742.3
FBXO42	ENST00000444116.1	c.887G>A	p.Ser296Asn	missense_variant	Exon 4 of 4	5		ENSP00000412416.1
FBXO42	ENST00000456164.5	c.887G>A	p.Ser296Asn	missense_variant	Exon 3 of 3	2		ENSP00000415663.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461876 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727236

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1733G>A (p.S578N) alteration is located in exon 10 (coding exon 9) of the FBXO42 gene. This alteration results from a G to A substitution at nucleotide position 1733, causing the serine (S) at amino acid position 578 to be replaced by an asparagine (N). 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	0.15
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.016	T;T;T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.83	T;.;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.90	L;.;.
PhyloP100		5.4
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	0.050	N;N;N
REVEL	Benign	0.14
Sift	Uncertain	0.021	D;D;D
Sift4G	Benign	1.0	T;.;.
Polyphen		0.97	D;.;.
Vest4		0.30
MutPred		0.23		Loss of phosphorylation at S578 (P = 0.0026);.;.;
MVP		0.082
MPC		0.30
ClinPred		0.71	D
GERP RS		5.5
Varity_R		0.12
gMVP		0.30
Mutation Taster		=82/18	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

Publications

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Other links and lift over

dbSNP: rs2081586387; hg19: chr1-16577586;