4-152335693-T-C

Variant names:

• chr4-152335693-T-C
• rs6535847
• NM_001349798.2:c.861+2109A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001349798.2(FBXW7):​c.861+2109A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.538 in 152,062 control chromosomes in the GnomAD database, including 24,983 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.54 (24983 hom., cov: 33)
• Consequence: FBXW7 NM_001349798.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.04
• Publications: 5 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 4-152335693-T-C is Benign according to our data. Variant chr4-152335693-T-C is described in ClinVar as Benign. ClinVar VariationId is 1291721.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.693 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXW7	NM_001349798.2	MANE Select	c.861+2109A>G		intron	N/A	NP_001336727.1
	FBXW7	NM_033632.3		c.861+2109A>G		intron	N/A	NP_361014.1
	FBXW7	NM_018315.5		c.621+2109A>G		intron	N/A	NP_060785.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXW7	ENST00000281708.10	TSL:1 MANE Select	c.861+2109A>G		intron	N/A	ENSP00000281708.3
	FBXW7	ENST00000603548.6	TSL:1	c.861+2109A>G		intron	N/A	ENSP00000474725.1
	FBXW7	ENST00000603841.1	TSL:1	c.861+2109A>G		intron	N/A	ENSP00000474971.1

Frequencies

GnomAD3 genomes AF: 0.539 AC: 81874 AN: 151944 Hom.: 24992 Cov.: 33

Gnomad AFR AF: 0.240

Gnomad AMI AF: 0.842

Gnomad AMR AF: 0.532

Gnomad ASJ AF: 0.563

Gnomad EAS AF: 0.487

Gnomad SAS AF: 0.591

Gnomad FIN AF: 0.659

Gnomad MID AF: 0.535

Gnomad NFE AF: 0.698

Gnomad OTH AF: 0.548

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.538 AC: 81871 AN: 152062 Hom.: 24983 Cov.: 33 AF XY: 0.535 AC XY: 39735 AN XY: 74306

African (AFR) AF: 0.240 AC: 9953 AN: 41490

American (AMR) AF: 0.532 AC: 8121 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.563 AC: 1952 AN: 3468

East Asian (EAS) AF: 0.487 AC: 2510 AN: 5156

South Asian (SAS) AF: 0.590 AC: 2849 AN: 4826

European-Finnish (FIN) AF: 0.659 AC: 6969 AN: 10580

Middle Eastern (MID) AF: 0.524 AC: 154 AN: 294

European-Non Finnish (NFE) AF: 0.698 AC: 47443 AN: 67960

Other (OTH) AF: 0.545 AC: 1152 AN: 2114

Alfa AF: 0.559 Hom.: 12468

Bravo AF: 0.517

Asia WGS AF: 0.497 AC: 1724 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Apr 28, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 21862670)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	3.6
DANN	Benign	0.65
PhyloP100		-1.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6535847; hg19: chr4-153256845;