Genetic Variant NM_018994.3:c.1733G>C (chr1-16251091-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.1733G>C(p.Ser578Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. S578N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

FBXO42
NM_018994.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.35

Publications

0 publications found

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=0.20083982).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXO42	NM_018994.3 link	c.1733G>C	p.Ser578Thr	missense_variant	Exon 10 of 10	ENST00000375592.8	NP_061867.1	Q6P3S6
FBXO42	XM_047422747.1 link	c.1733G>C	p.Ser578Thr	missense_variant	Exon 12 of 12		XP_047278703.1
FBXO42	XM_047422750.1 link	c.1733G>C	p.Ser578Thr	missense_variant	Exon 12 of 12		XP_047278706.1
FBXO42	XM_047422751.1 link	c.1733G>C	p.Ser578Thr	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.1733G>C	p.Ser578Thr	missense_variant	Exon 10 of 10	1	NM_018994.3	ENSP00000364742.3	Q6P3S6
FBXO42	ENST00000444116.1 link	c.887G>C	p.Ser296Thr	missense_variant	Exon 4 of 4	5		ENSP00000412416.1	X6RKU3
FBXO42	ENST00000456164.5 link	c.887G>C	p.Ser296Thr	missense_variant	Exon 3 of 3	2		ENSP00000415663.1	X6RKU3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461876

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112012

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.035

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.018

T;T;T

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.70

T;.;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.20

T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.90

L;.;.

PhyloP100

5.4

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.51

N;N;N

REVEL

Benign

0.16

Sift

Benign

0.059

T;D;D

Sift4G

Benign

0.28

T;.;.

Polyphen

0.92

P;.;.

Vest4

0.27

MutPred

0.13

Gain of sheet (P = 0.1208);.;.;

MVP

0.082

MPC

0.31

ClinPred

0.53

GERP RS

5.5

Varity_R

0.11

gMVP

0.28

Mutation Taster

=85/15

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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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NM_018994.3:c.1733G>C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over