2-47839485-T-A

Position:

chr2-47839485-T-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The ENST00000403359.8(FBXO11):c.376A>T(p.Thr126Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0042 in 1,613,956 control chromosomes in the GnomAD database, including 281 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T126A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.023 ( 144 hom., cov: 32)

Exomes 𝑓: 0.0023 ( 137 hom. )

Consequence

FBXO11
ENST00000403359.8 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3O:1

Conservation

PhyloP100: 1.57

Variant links:

Genes affected

FBXO11 (HGNC:13590): (F-box protein 11) This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbxs class. It can function as an arginine methyltransferase that symmetrically dimethylates arginine residues, and it acts as an adaptor protein to mediate the neddylation of p53, which leads to the suppression of p53 function. This gene is known to be down-regulated in melanocytes from patients with vitiligo, a skin disorder that results in depigmentation. Polymorphisms in this gene are associated with chronic otitis media with effusion and recurrent otitis media (COME/ROM), a hearing loss disorder, and the knockout of the homologous mouse gene results in the deaf mouse mutant Jeff (Jf), a single gene model of otitis media. Alternatively spliced transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jun 2010]

FBXO11 links:

FBXO11 (HGNC:):

FBXO11 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FBXO11. . Gene score misZ 4.3792 (greater than the threshold 3.09). Trascript score misZ 4.0886 (greater than threshold 3.09). GenCC has associacion of gene with intellectual developmental disorder with dysmorphic facies and behavioral abnormalities.

BP4

Computational evidence support a benign effect (MetaRNN=0.0016235709).

BP6

Variant 2-47839485-T-A is Benign according to our data. Variant chr2-47839485-T-A is described in ClinVar as [Benign]. Clinvar id is 134377.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0765 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBXO11	NM_001190274.2 linkuse as main transcript	c.376A>T	p.Thr126Ser	missense_variant	3/23	ENST00000403359.8	NP_001177203.1	Q86XK2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBXO11	ENST00000403359.8 linkuse as main transcript	c.376A>T	p.Thr126Ser	missense_variant	3/23	1	NM_001190274.2	ENSP00000384823.4		Q86XK2-1

Frequencies

GnomAD3 genomes

AF:

0.0225

AC:

3431

AN:

152202

Hom.:

143

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0788

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00746

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.0182

GnomAD3 exomes

AF:

0.00554

AC:

1389

AN:

250696

Hom.:

AF XY:

0.00400

AC XY:

542

AN XY:

135606

show subpopulations

Gnomad AFR exome

AF:

0.0793

Gnomad AMR exome

AF:

0.00249

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000328

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000203

Gnomad OTH exome

AF:

0.00180

GnomAD4 exome

AF:

0.00229

AC:

3344

AN:

1461636

Hom.:

137

Cov.:

AF XY:

0.00189

AC XY:

1373

AN XY:

727070

show subpopulations

Gnomad4 AFR exome

AF:

0.0820

Gnomad4 AMR exome

AF:

0.00327

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000131

Gnomad4 OTH exome

AF:

0.00470

GnomAD4 genome

AF:

0.0226

AC:

3440

AN:

152320

Hom.:

144

Cov.:

AF XY:

0.0218

AC XY:

1621

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.0787

Gnomad4 AMR

AF:

0.00745

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000235

Gnomad4 OTH

AF:

0.0180

Alfa

AF:

0.000996

Hom.:

Bravo

AF:

0.0257

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0820

AC:

361

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00702

AC:

852

EpiCase

AF:

0.000218

EpiControl

AF:

0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -

FBXO11-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 28, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not specified

Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Benign

0.83

DEOGEN2

Benign

0.054

.;T;T

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.56

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.84

T;T;T

MetaRNN

Benign

0.0016

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

.;N;.

MutationTaster

Benign

0.58

D;D;D;D

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-0.11

N;N;N

REVEL

Benign

0.029

Sift

Benign

0.93

T;T;T

Sift4G

Benign

0.73

T;T;.

Polyphen

0.038

.;B;.

Vest4

0.10

MutPred

0.17

.;Loss of catalytic residue at T126 (P = 0.0545);.;

MVP

0.43

MPC

0.33

ClinPred

0.012

GERP RS

1.4

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.0

Varity_R

0.030

gMVP

0.14

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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