Genetic Variant NM_001349798.2:c.1394G>A (chr4-152328232-C-T) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PM5PP2PP3_Moderate

The NM_001349798.2(FBXW7):c.1394G>A(p.Arg465His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R465C) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

FBXW7
NM_001349798.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.91

Publications

233 publications found

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 Gene-Disease associations (from GenCC):

developmental delay, hypotonia, and impaired language
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

FBXW7 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr4-152328233-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 376414.Status of the report is criteria_provided_single_submitter, 1 stars.

PP2

Missense variant in the FBXW7 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 24 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Gene score misZ: 3.7111 (above the threshold of 3.09). Trascript score misZ: 4.5266 (above the threshold of 3.09). GenCC associations: The gene is linked to developmental delay, hypotonia, and impaired language.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.887

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001349798.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FBXW7	NM_001349798.2	MANE Select	c.1394G>A	p.Arg465His	missense	Exon 11 of 14	NP_001336727.1
FBXW7	NM_033632.3		c.1394G>A	p.Arg465His	missense	Exon 9 of 12	NP_361014.1
FBXW7	NM_018315.5		c.1154G>A	p.Arg385His	missense	Exon 8 of 11	NP_060785.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FBXW7	ENST00000281708.10	TSL:1 MANE Select	c.1394G>A	p.Arg465His	missense	Exon 11 of 14	ENSP00000281708.3
FBXW7	ENST00000603548.6	TSL:1	c.1394G>A	p.Arg465His	missense	Exon 9 of 12	ENSP00000474725.1
FBXW7	ENST00000603841.1	TSL:1	c.1394G>A	p.Arg465His	missense	Exon 8 of 11	ENSP00000474971.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

231580

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1440986

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

716258

African (AFR)

AF:

0.00

AC:

AN:

31956

American (AMR)

AF:

0.00

AC:

AN:

41030

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25660

East Asian (EAS)

AF:

0.00

AC:

AN:

38058

South Asian (SAS)

AF:

0.00

AC:

AN:

82010

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53254

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5700

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1103746

Other (OTH)

AF:

0.00

AC:

AN:

59572

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.37

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Benign

0.72

LIST_S2

Pathogenic

0.99

M_CAP

Benign

0.028

MetaRNN

Pathogenic

0.89

MetaSVM

Benign

-0.68

MutationAssessor

Benign

1.3

PhyloP100

7.9

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-4.9

REVEL

Uncertain

0.56

Sift

Uncertain

0.0010

Sift4G

Benign

0.074

Polyphen

1.0

Vest4

0.79

MutPred

0.72

Loss of MoRF binding (P = 0.0346)

MVP

0.83

MPC

3.1

ClinPred

1.0

GERP RS

6.0

Varity_R

0.83

gMVP

0.69

Mutation Taster

=21/79

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over