10-101611302-G-C

Variant names:

• chr10-101611302-G-C
• rs2063780083
• NM_022039.4:c.1693C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022039.4(FBXW4):​c.1693C>G​(p.Gln565Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FBXW4 NM_022039.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.21

Genes affected

FBXW4 (HGNC:10847): (F-box and WD repeat domain containing 4) This gene is a member of the F-box/WD-40 gene family, which recruit specific target proteins through their WD-40 protein-protein binding domains for ubiquitin mediated degradation. In mouse, a highly similar protein is thought to be responsible for maintaining the apical ectodermal ridge of developing limb buds; disruption of the mouse gene results in the absence of central digits, underdeveloped or absent metacarpal/metatarsal bones and syndactyly. This phenotype is remarkably similar to split hand-split foot malformation in humans, a clinically heterogeneous condition with a variety of modes of transmission. An autosomal recessive form has been mapped to the chromosomal region where this gene is located, and complex rearrangements involving duplications of this gene and others have been associated with the condition. A pseudogene of this locus has been mapped to one of the introns of the BCR gene on chromosome 22. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09392214).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXW4	NM_022039.4	c.1693C>G	p.Gln565Glu	missense_variant	Exon 9 of 9	ENST00000331272.9	NP_071322.2
FBXW4	NM_001323541.2	c.967C>G	p.Gln323Glu	missense_variant	Exon 9 of 9		NP_001310470.1
FBXW4	NR_136613.2	n.1663C>G		non_coding_transcript_exon_variant	Exon 8 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBXW4	ENST00000331272.9	c.1693C>G	p.Gln565Glu	missense_variant	Exon 9 of 9	1	NM_022039.4	ENSP00000359149.3
FBXW4	ENST00000664783.1	c.1228C>G	p.Gln410Glu	missense_variant	Exon 9 of 9			ENSP00000499522.1
FBXW4	ENST00000470093.5	n.2547C>G		non_coding_transcript_exon_variant	Exon 4 of 4	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000936 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

May 07, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant has not been reported in the literature in individuals affected with FBXW4-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 410 of the FBXW4 protein (p.Gln410Glu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	19
DANN	Benign	0.94
DEOGEN2	Benign	0.024	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.094	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.010	N
REVEL	Benign	0.060
Sift	Benign	0.13	T
Sift4G	Benign	0.25	T
Polyphen		0.0	B
Vest4		0.052
MutPred		0.32		Gain of disorder (P = 0.1389);
MVP		0.68
MPC		0.44
ClinPred		0.027	T
GERP RS		2.3
Varity_R		0.047
gMVP		0.26

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: rs2063780083; hg19: chr10-103371059;