2-73264345-C-T

Position:

chr2-73264345-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001371389.2(FBXO41):c.1739G>A(p.Arg580His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000126 in 1,613,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R580C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

FBXO41
NM_001371389.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.25

Variant links:

Genes affected

FBXO41 (HGNC:29409): (F-box protein 41) This gene encodes a member of the F-box protein family, which is characterized by an approximately 40 amino acid motif, the F-box. F-box proteins constitute one of the four subunits of the SCF ubiquitin protein ligase complex that plays a role in phosphorylation-dependent ubiquitination. F-box proteins are divided into three classes depending on the interaction substrate domain each contains in addition to the F-box motif: FBXW proteins contain WD-40 domains, FBXL proteins contain leucine-rich repeats, and FBXO proteins contain either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the FBXO class. [provided by RefSeq, Feb 2014]

FBXO41 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15490645).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBXO41	NM_001371389.2 linkuse as main transcript	c.1739G>A	p.Arg580His	missense_variant	6/13	ENST00000520530.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
FBXO41	ENST00000520530.3 linkuse as main transcript	c.1739G>A	p.Arg580His	missense_variant	6/13	5	NM_001371389.2	P1
FBXO41	ENST00000295133.9 linkuse as main transcript	c.1739G>A	p.Arg580His	missense_variant	5/12	1		P1
FBXO41	ENST00000521871.5 linkuse as main transcript	c.1739G>A	p.Arg580His	missense_variant	6/13	5		P1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000129

AC:

AN:

248460

Hom.:

AF XY:

0.000141

AC XY:

AN XY:

134956

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.000299

Gnomad EAS exome

AF:

0.000669

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000534

Gnomad OTH exome

AF:

0.000331

GnomAD4 exome

AF:

0.000131

AC:

192

AN:

1461356

Hom.:

Cov.:

AF XY:

0.000143

AC XY:

104

AN XY:

726968

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.000756

Gnomad4 SAS exome

AF:

0.000185

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000116

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000722

AC:

AN:

152326

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.000125

ExAC

AF:

0.000148

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 03, 2024

The c.1739G>A (p.R580H) alteration is located in exon 5 (coding exon 5) of the FBXO41 gene. This alteration results from a G to A substitution at nucleotide position 1739, causing the arginine (R) at amino acid position 580 to be replaced by a histidine (H). 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

0.29

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.27

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.012

T;T;T

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Benign

0.74

LIST_S2

Uncertain

0.97

D;.;.

M_CAP

Benign

0.023

MetaRNN

Benign

0.15

T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.6

L;L;L

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-1.1

N;N;.

REVEL

Benign

0.22

Sift

Benign

0.034

D;D;.

Sift4G

Uncertain

0.033

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.56

MVP

0.60

MPC

1.1

ClinPred

0.12

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.089

gMVP

0.48

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over