1-16251383-A-G

Position:

• chr1-16251383-A-G

Variant summary

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

The NM_018994.3(FBXO42):​c.1441T>C​(p.Ser481Pro) 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. 14/21 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: 0.227

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=0.060717642).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBXO42	NM_018994.3	c.1441T>C	p.Ser481Pro	missense_variant	10/10	ENST00000375592.8
FBXO42	XM_047422747.1	c.1441T>C	p.Ser481Pro	missense_variant	12/12
FBXO42	XM_047422750.1	c.1441T>C	p.Ser481Pro	missense_variant	12/12
FBXO42	XM_047422751.1	c.1441T>C	p.Ser481Pro	missense_variant	12/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBXO42	ENST00000375592.8	c.1441T>C	p.Ser481Pro	missense_variant	10/10	1	NM_018994.3	P1
FBXO42	ENST00000444116.1	c.595T>C	p.Ser199Pro	missense_variant	4/4	5
FBXO42	ENST00000456164.5	c.595T>C	p.Ser199Pro	missense_variant	3/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Jun 29, 2023

The c.1441T>C (p.S481P) alteration is located in exon 10 (coding exon 9) of the FBXO42 gene. This alteration results from a T to C substitution at nucleotide position 1441, causing the serine (S) at amino acid position 481 to be replaced by a proline (P). 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	0.057
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.024	T;T;T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.66	T;.;T
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.061	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;.;.
MutationTaster	Benign	0.99	N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.4	N;N;N
REVEL	Benign	0.051
Sift	Uncertain	0.023	D;D;D
Sift4G	Uncertain	0.053	T;.;.
Polyphen		0.0	B;.;.
Vest4		0.035
MutPred		0.23		Loss of sheet (P = 0.0228);.;.;
MVP		0.35
MPC		0.32
ClinPred		0.091	T
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.25

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: chr1-16577878;