chr4-152382202-A-C

Variant names:

• chr4-152382202-A-C
• rs576143888
• ENST00000296555.11:c.134T>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP2 BP4_Strong BS1_Supporting BS2

The ENST00000296555.11(FBXW7):​c.134T>G​(p.Phe45Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00024 in 1,550,294 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (7 hom.)
• Consequence: FBXW7 ENST00000296555.11 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 6.79
• Publications: 1 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 -8 ACMG points.

• 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: 4.6663 (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=0.010555834).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000217 (33/152248) while in subpopulation SAS AF = 0.00643 (31/4818). AF 95% confidence interval is 0.00466. There are 0 homozygotes in GnomAd4. There are 24 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 33 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000296555.11. 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.501+29101T>G		intron	N/A	NP_001336727.1
	FBXW7	NM_001013415.2		c.134T>G	p.Phe45Cys	missense	Exon 1 of 11	NP_001013433.1
	FBXW7	NM_033632.3		c.501+29101T>G		intron	N/A	NP_361014.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXW7	ENST00000296555.11	TSL:1	c.134T>G	p.Phe45Cys	missense	Exon 1 of 11	ENSP00000296555.4
	FBXW7	ENST00000281708.10	TSL:1 MANE Select	c.501+29101T>G		intron	N/A	ENSP00000281708.3
	FBXW7	ENST00000603548.6	TSL:1	c.501+29101T>G		intron	N/A	ENSP00000474725.1

Frequencies

GnomAD3 genomes AF: 0.000223 AC: 34 AN: 152130 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00664

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000588 AC: 130 AN: 221028 AF XY: 0.000775

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000787

GnomAD4 exome AF: 0.000242 AC: 339 AN: 1398046 Hom.: 7 Cov.: 30 AF XY: 0.000348 AC XY: 241 AN XY: 693384

African (AFR) AF: 0.0000324 AC: 1 AN: 30882

American (AMR) AF: 0.00 AC: 0 AN: 39186

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24580

East Asian (EAS) AF: 0.00 AC: 0 AN: 36604

South Asian (SAS) AF: 0.00427 AC: 313 AN: 73370

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51692

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5566

European-Non Finnish (NFE) AF: 0.00000185 AC: 2 AN: 1078814

Other (OTH) AF: 0.000401 AC: 23 AN: 57352

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152248 Hom.: 0 Cov.: 32 AF XY: 0.000322 AC XY: 24 AN XY: 74440

African (AFR) AF: 0.0000481 AC: 2 AN: 41568

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00643 AC: 31 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000139 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.000708 AC: 86

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not specified Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	20
DANN	Benign	0.97
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.49	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.97	T
PhyloP100		6.8
PROVEAN	Benign	0.21	N
REVEL	Benign	0.13
Sift	Uncertain	0.017	D
Sift4G	Benign	0.18	T
Polyphen		0.53	P
Vest4		0.83
MutPred		0.34		Gain of loop (P = 0.0045)
MVP		0.66
ClinPred		0.17	T
GERP RS		5.7
PromoterAI		0.016	Neutral
Mutation Taster		=88/12	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: rs576143888; hg19: chr4-153303354;