rs6842544

Positions:

chr4-152411407-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2BP4_StrongBP6_ModerateBS1BS2

The NM_001349798.2(FBXW7):c.397A>G(p.Arg133Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000934 in 1,613,712 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts 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.

Frequency

Genomes: 𝑓 0.0054 ( 7 hom., cov: 32)

Exomes 𝑓: 0.00047 ( 5 hom. )

Consequence

FBXW7
NM_001349798.2 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1O:1

Conservation

PhyloP100: 2.24

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 -13 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=0.004651934).

BP6

Variant 4-152411407-T-C is Benign according to our data. Variant chr4-152411407-T-C is described in ClinVar as [Benign]. Clinvar id is 134382.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00544 (828/152218) while in subpopulation AFR AF= 0.0187 (777/41556). AF 95% confidence interval is 0.0176. There are 7 homozygotes in gnomad4. There are 392 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 828 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBXW7	NM_001349798.2 linkuse as main transcript	c.397A>G	p.Arg133Gly	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.397A>G	p.Arg133Gly	missense_variant	4/14	1	NM_001349798.2	ENSP00000281708.3		Q969H0-1

Frequencies

GnomAD3 genomes

AF:

0.00544

AC:

828

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0188

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00256

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00480

GnomAD3 exomes

AF:

0.00144

AC:

360

AN:

250428

Hom.:

AF XY:

0.00105

AC XY:

142

AN XY:

135316

show subpopulations

Gnomad AFR exome

AF:

0.0197

Gnomad AMR exome

AF:

0.000872

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:

0.0000442

Gnomad OTH exome

AF:

0.000820

GnomAD4 exome

AF:

0.000465

AC:

680

AN:

1461494

Hom.:

Cov.:

AF XY:

0.000432

AC XY:

314

AN XY:

727036

show subpopulations

Gnomad4 AFR exome

AF:

0.0161

Gnomad4 AMR exome

AF:

0.00110

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:

0.0000144

Gnomad4 OTH exome

AF:

0.00121

GnomAD4 genome

AF:

0.00544

AC:

828

AN:

152218

Hom.:

Cov.:

AF XY:

0.00527

AC XY:

392

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.0187

Gnomad4 AMR

AF:

0.00255

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00475

Alfa

AF:

0.00122

Hom.:

Bravo

AF:

0.00651

ESP6500AA

AF:

0.0182

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00180

AC:

219

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 12, 2024

- -

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

0.12

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.14

T;T;T;T;T

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.84

.;.;T;T;T

MetaRNN

Benign

0.0047

T;T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.90

L;L;L;.;.

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.40

.;N;.;.;.

REVEL

Benign

0.21

Sift

Uncertain

0.024

.;D;.;.;.

Sift4G

Benign

0.29

T;T;T;T;.

Polyphen

0.97

D;D;D;.;.

Vest4

0.73

MVP

0.51

MPC

0.53

ClinPred

0.029

GERP RS

4.3

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.6

Varity_R

0.10

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

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