4-152322939-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PS1_Moderate PM2 PM5 PP2 PP5

The NM_001349798.2(FBXW7):c.2066G>A(p.Arg689Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,480 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R689W) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FBXW7 NM_001349798.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.87

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 Likely_pathogenic. Variant got 8 ACMG points.

• PS1: Transcript NM_001349798.2 (FBXW7) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-152322940-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2582613.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, FBXW7
• PP5: Variant 4-152322939-C-T is Pathogenic according to our data. Variant chr4-152322939-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 1702999.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBXW7	NM_001349798.2	c.2066G>A	p.Arg689Gln	missense_variant	14/14	ENST00000281708.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBXW7	ENST00000281708.10	c.2066G>A	p.Arg689Gln	missense_variant	14/14	1	NM_001349798.2	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461480 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727058

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Developmental delay, hypotonia, and impaired language Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 26, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Benign	-0.19
Cadd	Pathogenic	34
Dann	Uncertain	1.0
DEOGEN2	Benign	0.41	T;.;T;.;.;T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.047	D
MetaRNN	Uncertain	0.72	D;D;D;D;D;D
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.7	M;.;M;.;.;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.86	D
Sift4G	Uncertain	0.0070	D;D;D;.;D;D
Polyphen		1.0	D;D;D;D;D;D
Vest4		0.85
MutPred		0.41		Gain of sheet (P = 0.0477);.;Gain of sheet (P = 0.0477);.;.;Gain of sheet (P = 0.0477);
MVP		0.76
MPC		2.6
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.84
gMVP		0.78

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-153244091; COSMIC: COSV55900091; COSMIC: COSV55900091;