Variant 4-152322940-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PS1_ModeratePM2PM5PP2PP3_ModeratePP5_Moderate

The NM_001349798.2(FBXW7):c.2065C>T(p.Arg689Trp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R689Q) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

FBXW7
NM_001349798.2 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 4.00

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:

FBXW7 (HGNC:):

FBXW7 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PS1

Transcript NM_001349798.2 (FBXW7) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.85

PP5

Variant 4-152322940-G-A is Pathogenic according to our data. Variant chr4-152322940-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2582613.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBXW7	NM_001349798.2 linkuse as main transcript	c.2065C>T	p.Arg689Trp	missense_variant	14/14	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.2065C>T	p.Arg689Trp	missense_variant	14/14	1	NM_001349798.2	ENSP00000281708.3		Q969H0-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Developmental delay, hypotonia, and impaired language

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 02, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.46

T;.;T;.;.;T

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

1.0

.;D;.;.;D;D

M_CAP

Benign

0.082

MetaRNN

Pathogenic

0.85

D;D;D;D;D;D

MetaSVM

Benign

-0.84

MutationAssessor

Uncertain

2.7

M;.;M;.;.;M

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-7.7

.;D;D;.;D;.

REVEL

Uncertain

0.35

Sift

Pathogenic

0.0

.;D;D;.;D;.

Sift4G

Pathogenic

0.0

D;D;D;.;D;D

Polyphen

1.0

D;D;D;D;D;D

Vest4

0.91

MutPred

0.47

Loss of disorder (P = 0.0242);.;Loss of disorder (P = 0.0242);.;.;Loss of disorder (P = 0.0242);

MVP

0.75

MPC

2.8

ClinPred

1.0

GERP RS

5.7

Varity_R

0.87

gMVP

0.88

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over