rs747241612

Variant names:

• chr4-152326215-G-A
• rs747241612
• NM_001349798.2:c.1435C>T

Your query was ambiguous. Multiple possible variants found:

• chr4-152326215-G-A
• chr4-152326215-G-C
• chr4-152326215-G-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_033632.3(FBXW7):​c.1435C>T​(p.Arg479*) variant causes a stop gained change. 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. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBXW7 NM_033632.3 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.71
• Publications: 0 publications found

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)

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033632.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXW7	NM_001349798.2	MANE Select	c.1435C>T	p.Arg479*	stop_gained	Exon 12 of 14	NP_001336727.1
	FBXW7	NM_033632.3		c.1435C>T	p.Arg479*	stop_gained	Exon 10 of 12	NP_361014.1
	FBXW7	NM_018315.5		c.1195C>T	p.Arg399*	stop_gained	Exon 9 of 11	NP_060785.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXW7	ENST00000281708.10	TSL:1 MANE Select	c.1435C>T	p.Arg479*	stop_gained	Exon 12 of 14	ENSP00000281708.3
	FBXW7	ENST00000603548.6	TSL:1	c.1435C>T	p.Arg479*	stop_gained	Exon 10 of 12	ENSP00000474725.1
	FBXW7	ENST00000603841.1	TSL:1	c.1435C>T	p.Arg479*	stop_gained	Exon 9 of 11	ENSP00000474971.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		5.7
Vest4		0.93
GERP RS		4.8
Mutation Taster		=2/198	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.27		Position offset: 16

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs747241612; hg19: chr4-153247367; COSMIC: COSV55894141; COSMIC: COSV55894141;