4-152324117-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001349798.2(FBXW7):c.1855+67C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0541 in 1,243,668 control chromosomes in the GnomAD database, including 2,177 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.044 (188 hom., cov: 32)
  • Exomes 𝑓: 0.056 (1989 hom.)
• Consequence: FBXW7 NM_001349798.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.483

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 4-152324117-G-A is Benign according to our data. Variant chr4-152324117-G-A is described in ClinVar as [Benign]. Clinvar id is 1263716.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0632 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBXW7	NM_001349798.2	c.1855+67C>T		intron_variant		ENST00000281708.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBXW7	ENST00000281708.10	c.1855+67C>T		intron_variant		1	NM_001349798.2	P4

Frequencies

GnomAD3 genomes AF: 0.0438 AC: 6652 AN: 151956 Hom.: 188 Cov.: 32

Gnomad AFR AF: 0.0116

Gnomad AMI AF: 0.0505

Gnomad AMR AF: 0.0387

Gnomad ASJ AF: 0.0159

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00831

Gnomad FIN AF: 0.0885

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0648

Gnomad OTH AF: 0.0454

GnomAD4 exome AF: 0.0556 AC: 60681 AN: 1091594 Hom.: 1989 Cov.: 14 AF XY: 0.0543 AC XY: 30063 AN XY: 553648

Gnomad4 AFR exome AF: 0.00982

Gnomad4 AMR exome AF: 0.0239

Gnomad4 ASJ exome AF: 0.0163

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00882

Gnomad4 FIN exome AF: 0.0806

Gnomad4 NFE exome AF: 0.0656

Gnomad4 OTH exome AF: 0.0506

GnomAD4 genome AF: 0.0437 AC: 6651 AN: 152074 Hom.: 188 Cov.: 32 AF XY: 0.0432 AC XY: 3207 AN XY: 74320

Gnomad4 AFR AF: 0.0116

Gnomad4 AMR AF: 0.0387

Gnomad4 ASJ AF: 0.0159

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00852

Gnomad4 FIN AF: 0.0885

Gnomad4 NFE AF: 0.0648

Gnomad4 OTH AF: 0.0449

Alfa AF: 0.0566 Hom.: 282

Bravo AF: 0.0383

Asia WGS AF: 0.00693 AC: 25 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 12, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	6.4
Dann	Benign	0.39

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

LitVar

Other links and lift over

dbSNP: rs35260882; hg19: chr4-153245269;