10-101611339-AT-GA

Variant names:

• chr10-101611339-AT-GA
• NM_022039.4:c.1655_1656delATinsTC
• FBXW4 p.Tyr552Phe

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_022039.4(FBXW4):​c.1655_1656delATinsTC​(p.Tyr552Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FBXW4 NM_022039.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.37
• Publications: 0 publications found

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]

FBXW4 Gene-Disease associations (from GenCC):

• split hand-foot malformation 3

  Inheritance: AD Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022039.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXW4	NM_022039.4	MANE Select	c.1655_1656delATinsTC	p.Tyr552Phe	missense	N/A	NP_071322.2	A0A5F9UQ55
	FBXW4	NM_001323541.2		c.929_930delATinsTC	p.Tyr310Phe	missense	N/A	NP_001310470.1
	FBXW4	NR_136613.2		n.1625_1626delATinsTC		non_coding_transcript_exon	Exon 8 of 8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXW4	ENST00000331272.9	TSL:1 MANE Select	c.1655_1656delATinsTC	p.Tyr552Phe	missense	N/A	ENSP00000359149.3	A0A5F9UQ55
	FBXW4	ENST00000945850.1		c.1727_1728delATinsTC	p.Tyr576Phe	missense	N/A	ENSP00000615909.1
	FBXW4	ENST00000945851.1		c.1706_1707delATinsTC	p.Tyr569Phe	missense	N/A	ENSP00000615910.1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.4

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr10-103371096;