rs147025249

Positions:

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_001349798.2(FBXW7):c.479C>T(p.Pro160Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000482 in 1,609,808 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.0025 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00027 ( 0 hom. )

Consequence

FBXW7
NM_001349798.2 missense

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1O:1

Conservation

PhyloP100: 5.88

Variant links:

Genes affected

FBXW7 (HGNC:16712): (F-box and WD repeat domain containing 7) 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 was previously referred to as FBX30, and belongs to the Fbws class; in addition to an F-box, this protein contains 7 tandem WD40 repeats. This protein binds directly to cyclin E and probably targets cyclin E for ubiquitin-mediated degradation. Mutations in this gene are detected in ovarian and breast cancer cell lines, implicating the gene's potential role in the pathogenesis of human cancers. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2012]

FBXW7 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FBXW7. . Gene score misZ 3.7111 (greater than the threshold 3.09). Trascript score misZ 4.5266 (greater than threshold 3.09). GenCC has associacion of gene with developmental delay, hypotonia, and impaired language.

BP4

Computational evidence support a benign effect (MetaRNN=0.0060050488).

BP6

Variant 4-152411325-G-A is Benign according to our data. Variant chr4-152411325-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 134385.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0025 (381/152178) while in subpopulation AFR AF= 0.00811 (337/41532). AF 95% confidence interval is 0.0074. There are 3 homozygotes in gnomad4. There are 174 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 381 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBXW7	NM_001349798.2 linkuse as main transcript	c.479C>T	p.Pro160Leu	missense_variant	4/14	ENST00000281708.10	NP_001336727.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBXW7	ENST00000281708.10 linkuse as main transcript	c.479C>T	p.Pro160Leu	missense_variant	4/14	1	NM_001349798.2	ENSP00000281708.3		Q969H0-1

Frequencies

GnomAD3 genomes

AF:

0.00249

AC:

379

AN:

152060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00809

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00223

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:

0.0000441

Gnomad OTH

AF:

0.00336

GnomAD3 exomes

AF:

0.000655

AC:

162

AN:

247468

Hom.:

AF XY:

0.000374

AC XY:

AN XY:

133614

show subpopulations

Gnomad AFR exome

AF:

0.00710

Gnomad AMR exome

AF:

0.00106

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000446

Gnomad OTH exome

AF:

0.000999

GnomAD4 exome

AF:

0.000271

AC:

395

AN:

1457630

Hom.:

Cov.:

AF XY:

0.000221

AC XY:

160

AN XY:

724736

show subpopulations

Gnomad4 AFR exome

AF:

0.00599

Gnomad4 AMR exome

AF:

0.00113

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000658

Gnomad4 OTH exome

AF:

0.00113

GnomAD4 genome

AF:

0.00250

AC:

381

AN:

152178

Hom.:

Cov.:

AF XY:

0.00234

AC XY:

174

AN XY:

74406

show subpopulations

Gnomad4 AFR

AF:

0.00811

Gnomad4 AMR

AF:

0.00223

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00332

Alfa

AF:

0.000445

Hom.:

Bravo

AF:

0.00285

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00658

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000659

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

FBXW7-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 20, 2019

This variant is classified as likely 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

0.081

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

T;T;T;T

Eigen

Benign

-0.0084

Eigen_PC

Benign

0.22

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.85

.;.;T;T

M_CAP

Benign

0.0076

MetaRNN

Benign

0.0060

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.34

N;N;N;.

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.6

.;N;.;.

REVEL

Benign

0.082

Sift

Uncertain

0.0040

.;D;.;.

Sift4G

Benign

0.38

T;T;T;D

Polyphen

0.0

B;B;B;.

Vest4

0.21

MVP

0.33

MPC

0.42

ClinPred

0.027

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.11

gMVP

0.052

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

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