4-152322172-G-C

Variant names:

• chr4-152322172-G-C
• rs4399968
• NM_001349798.2:c.*709C>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BS1 BS2

The NM_001349798.2(FBXW7):​c.*709C>G variant causes a 3 prime UTR change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00147 in 233,280 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (0 hom.)
• Consequence: FBXW7 NM_001349798.2 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.61
• Publications: 3 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00143 (218/152186) while in subpopulation NFE AF = 0.0029 (197/67984). AF 95% confidence interval is 0.00257. There are 0 homozygotes in GnomAd4. There are 91 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 218 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXW7	NM_001349798.2	c.*709C>G		3_prime_UTR_variant	Exon 14 of 14	ENST00000281708.10	NP_001336727.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBXW7	ENST00000281708.10	c.*709C>G		3_prime_UTR_variant	Exon 14 of 14	1	NM_001349798.2	ENSP00000281708.3
FBXW7	ENST00000603548.6	c.*709C>G		3_prime_UTR_variant	Exon 12 of 12	1		ENSP00000474725.1
FBXW7	ENST00000296555.11	c.*709C>G		3_prime_UTR_variant	Exon 11 of 11	1		ENSP00000296555.4
FBXW7	ENST00000393956.9	c.*709C>G		3_prime_UTR_variant	Exon 11 of 11	2		ENSP00000377528.4

Frequencies

GnomAD3 genomes AF: 0.00143 AC: 218 AN: 152068 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00290

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00154 AC: 125 AN: 81094 Hom.: 0 Cov.: 0 AF XY: 0.00190 AC XY: 71 AN XY: 37376

African (AFR) AF: 0.000258 AC: 1 AN: 3874

American (AMR) AF: 0.000401 AC: 1 AN: 2494

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5094

East Asian (EAS) AF: 0.00 AC: 0 AN: 11370

South Asian (SAS) AF: 0.00 AC: 0 AN: 700

European-Finnish (FIN) AF: 0.00207 AC: 1 AN: 484

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 492

European-Non Finnish (NFE) AF: 0.00221 AC: 110 AN: 49846

Other (OTH) AF: 0.00178 AC: 12 AN: 6740

GnomAD4 genome AF: 0.00143 AC: 218 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.00122 AC XY: 91 AN XY: 74398

African (AFR) AF: 0.000313 AC: 13 AN: 41536

American (AMR) AF: 0.000458 AC: 7 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.0000944 AC: 1 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00290 AC: 197 AN: 67984

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00143 Hom.: 0

Bravo AF: 0.00138

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	17
DANN	Benign	0.91
PhyloP100		8.6
Mutation Taster		=91/9	polymorphism

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: rs4399968; hg19: chr4-153243324;