rs12069239

Positions:

• chr1-16251413-G-C
• chr1-16251413-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018994.3(FBXO42):​c.1411C>G​(p.Pro471Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.349 in 1,613,826 control chromosomes in the GnomAD database, including 102,988 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.35 (10043 hom., cov: 32)
  • Exomes 𝑓: 0.35 (92945 hom.)
• Consequence: FBXO42 NM_018994.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.318

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001695782).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.419 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBXO42	NM_018994.3	c.1411C>G	p.Pro471Ala	missense_variant	10/10	ENST00000375592.8	NP_061867.1
FBXO42	XM_047422747.1	c.1411C>G	p.Pro471Ala	missense_variant	12/12		XP_047278703.1
FBXO42	XM_047422750.1	c.1411C>G	p.Pro471Ala	missense_variant	12/12		XP_047278706.1
FBXO42	XM_047422751.1	c.1411C>G	p.Pro471Ala	missense_variant	12/12		XP_047278707.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBXO42	ENST00000375592.8	c.1411C>G	p.Pro471Ala	missense_variant	10/10	1	NM_018994.3	ENSP00000364742	P1
FBXO42	ENST00000444116.1	c.565C>G	p.Pro189Ala	missense_variant	4/4	5		ENSP00000412416
FBXO42	ENST00000456164.5	c.565C>G	p.Pro189Ala	missense_variant	3/3	2		ENSP00000415663

Frequencies

GnomAD3 genomes AF: 0.354 AC: 53767 AN: 151890 Hom.: 10024 Cov.: 32

Gnomad AFR AF: 0.424

Gnomad AMI AF: 0.275

Gnomad AMR AF: 0.262

Gnomad ASJ AF: 0.289

Gnomad EAS AF: 0.185

Gnomad SAS AF: 0.163

Gnomad FIN AF: 0.338

Gnomad MID AF: 0.245

Gnomad NFE AF: 0.367

Gnomad OTH AF: 0.333

GnomAD3 exomes AF: 0.297 AC: 74578 AN: 250894 Hom.: 12347 AF XY: 0.293 AC XY: 39841 AN XY: 135746

Gnomad AFR exome AF: 0.434

Gnomad AMR exome AF: 0.176

Gnomad ASJ exome AF: 0.292

Gnomad EAS exome AF: 0.184

Gnomad SAS exome AF: 0.155

Gnomad FIN exome AF: 0.338

Gnomad NFE exome AF: 0.363

Gnomad OTH exome AF: 0.316

GnomAD4 exome AF: 0.348 AC: 509312 AN: 1461818 Hom.: 92945 Cov.: 57 AF XY: 0.342 AC XY: 248964 AN XY: 727206

Gnomad4 AFR exome AF: 0.428

Gnomad4 AMR exome AF: 0.184

Gnomad4 ASJ exome AF: 0.294

Gnomad4 EAS exome AF: 0.164

Gnomad4 SAS exome AF: 0.160

Gnomad4 FIN exome AF: 0.331

Gnomad4 NFE exome AF: 0.377

Gnomad4 OTH exome AF: 0.331

GnomAD4 genome AF: 0.354 AC: 53823 AN: 152008 Hom.: 10043 Cov.: 32 AF XY: 0.346 AC XY: 25686 AN XY: 74314

Gnomad4 AFR AF: 0.424

Gnomad4 AMR AF: 0.262

Gnomad4 ASJ AF: 0.289

Gnomad4 EAS AF: 0.185

Gnomad4 SAS AF: 0.163

Gnomad4 FIN AF: 0.338

Gnomad4 NFE AF: 0.367

Gnomad4 OTH AF: 0.329

Alfa AF: 0.331 Hom.: 5159

Bravo AF: 0.354

TwinsUK AF: 0.390 AC: 1446

ALSPAC AF: 0.375 AC: 1445

ESP6500AA AF: 0.423 AC: 1864

ESP6500EA AF: 0.359 AC: 3084

ExAC AF: 0.303 AC: 36844

Asia WGS AF: 0.191 AC: 667 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.043
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.84
DANN	Benign	0.46
DEOGEN2	Benign	0.015	T;T;T
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.12	T;.;T
MetaRNN	Benign	0.0017	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.0	N;.;.
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.080	N;N;N
REVEL	Benign	0.031
Sift	Benign	0.89	T;T;T
Sift4G	Benign	0.79	T;.;.
Polyphen		0.0	B;.;.
Vest4		0.013
MPC		0.25
ClinPred		0.00039	T
GERP RS		0.74
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.010
gMVP		0.11

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: rs12069239; hg19: chr1-16577908; COSMIC: COSV65044788;