NM_001349798.2:c.1875T>G

Variant names:

• chr4-152323130-A-C
• NM_001349798.2:c.1875T>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001349798.2(FBXW7):​c.1875T>G​(p.Ser625Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 0.981

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 Uncertain_significance. Variant got 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXW7	NM_001349798.2	c.1875T>G	p.Ser625Arg	missense_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.1875T>G	p.Ser625Arg	missense_variant	Exon 14 of 14	1	NM_001349798.2	ENSP00000281708.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jan 24, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015); Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.059	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T;.;T;.;.;T
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Pathogenic	0.98	.;D;.;.;D;D
M_CAP	Benign	0.070	D
MetaRNN	Uncertain	0.74	D;D;D;D;D;D
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.97	L;.;L;.;.;L
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-4.9	.;D;D;.;D;.
REVEL	Uncertain	0.46
Sift	Uncertain	0.0040	.;D;D;.;D;.
Sift4G	Benign	0.10	T;T;T;.;T;T
Polyphen		1.0	D;D;D;D;D;D
Vest4		0.81
MutPred		0.68		Loss of ubiquitination at K622 (P = 0.0435);.;Loss of ubiquitination at K622 (P = 0.0435);.;.;Loss of ubiquitination at K622 (P = 0.0435);
MVP		0.71
MPC		2.9
ClinPred		0.99	D
GERP RS		1.9
Varity_R		0.84
gMVP		0.90

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: chr4-153244282;