1-11661260-C-G

Position:

• chr1-11661260-C-G

Variant summary

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

The NM_033182.7(FBXO44):​c.755C>G​(p.Pro252Arg) 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: FBXO44 NM_033182.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.53

Genes affected

FBXO44 (HGNC:24847): (F-box protein 44) 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 the 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 belongs to the Fbxs class. It is also a member of the NFB42 (neural F Box 42 kDa) family, similar to F-box only protein 2 and F-box only protein 6. Several alternatively spliced transcript variants encoding two distinct isoforms have been found for this gene. [provided by RefSeq, Feb 2015]

FBXO44 (HGNC:):

MAD2L2 (HGNC:6764): (mitotic arrest deficient 2 like 2) The protein encoded by this gene is a component of the mitotic spindle assembly checkpoint that prevents the onset of anaphase until all chromosomes are properly aligned at the metaphase plate. The encoded protein, which is similar to MAD2L1, is capable of interacting with ADAM9, ADAM15, REV1, and REV3 proteins. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBXO44	NM_033182.7	c.755C>G	p.Pro252Arg	missense_variant	6/6	ENST00000251547.10	NP_149438.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBXO44	ENST00000251547.10	c.755C>G	p.Pro252Arg	missense_variant	6/6	1	NM_033182.7	ENSP00000251547.5

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 specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2023

The c.755C>G (p.P252R) alteration is located in exon 7 (coding exon 5) of the FBXO44 gene. This alteration results from a C to G substitution at nucleotide position 755, causing the proline (P) at amino acid position 252 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	0.0047	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T;T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.61	T;.
M_CAP	Benign	0.075	D
MetaRNN	Uncertain	0.62	D;D
MetaSVM	Benign	-0.76	T
MutationAssessor	Pathogenic	3.3	M;M
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-4.3	D;D
REVEL	Benign	0.21
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.97	D;D
Vest4		0.47
MutPred		0.68		Loss of glycosylation at T249 (P = 0.018);Loss of glycosylation at T249 (P = 0.018);
MVP		0.40
MPC		1.1
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr1-11721317;