chr4-152337903-C-T

Variant names:

• chr4-152337903-C-T
• rs2126585179
• NM_001349798.2:c.760G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001349798.2(FBXW7):​c.760G>A​(p.Asp254Asn) 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 benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBXW7 NM_001349798.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.85
• 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-AS1 (HGNC:52397): (FBXW7 antisense RNA 1) Located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.31023413).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXW7	NM_001349798.2	MANE Select	c.760G>A	p.Asp254Asn	missense	Exon 7 of 14	NP_001336727.1	Q969H0-1
	FBXW7	NM_033632.3		c.760G>A	p.Asp254Asn	missense	Exon 5 of 12	NP_361014.1	Q969H0-1
	FBXW7	NM_018315.5		c.520G>A	p.Asp174Asn	missense	Exon 4 of 11	NP_060785.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXW7	ENST00000281708.10	TSL:1 MANE Select	c.760G>A	p.Asp254Asn	missense	Exon 7 of 14	ENSP00000281708.3	Q969H0-1
	FBXW7	ENST00000603548.6	TSL:1	c.760G>A	p.Asp254Asn	missense	Exon 5 of 12	ENSP00000474725.1	Q969H0-1
	FBXW7	ENST00000603841.1	TSL:1	c.760G>A	p.Asp254Asn	missense	Exon 4 of 11	ENSP00000474971.1	Q969H0-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.1	L
PhyloP100		7.8
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.22
Sift	Benign	0.036	D
Sift4G	Uncertain	0.056	T
Polyphen		0.34	B
Vest4		0.67
MutPred		0.44		Gain of catalytic residue at D254 (P = 0.0438)
MVP		0.40
MPC		0.64
ClinPred		0.76	D
GERP RS		5.8
Varity_R		0.44
gMVP		0.57
Mutation Taster		=13/87	disease causing

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: rs2126585179; hg19: chr4-153259055;