4-15625688-C-T

Variant names:

• chr4-15625688-C-T
• NM_012161.4:c.1414G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012161.4(FBXL5):​c.1414G>A​(p.Glu472Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 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: FBXL5 NM_012161.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.43
• Publications: 0 publications found

Genes affected

FBXL5 (HGNC:13602): (F-box and leucine rich repeat protein 5) 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 belongs to the Fbls class and, in addition to an F-box, contains several tandem leucine-rich repeats. Alternatively spliced transcript variants have been described for this locus. [provided by RefSeq, Aug 2010]

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18136132).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012161.4. 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
	FBXL5	NM_012161.4	MANE Select	c.1414G>A	p.Glu472Lys	missense	Exon 9 of 11	NP_036293.1	Q9UKA1-1
	FBXL5	NM_001193534.2		c.1411G>A	p.Glu471Lys	missense	Exon 9 of 11	NP_001180463.1
	FBXL5	NM_001193535.2		c.1363G>A	p.Glu455Lys	missense	Exon 9 of 11	NP_001180464.1	Q9UKA1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXL5	ENST00000341285.8	TSL:1 MANE Select	c.1414G>A	p.Glu472Lys	missense	Exon 9 of 11	ENSP00000344866.3	Q9UKA1-1
	FBXL5	ENST00000412094.6	TSL:1	c.1363G>A	p.Glu455Lys	missense	Exon 9 of 11	ENSP00000408679.2	Q9UKA1-2
	FBXL5	ENST00000513163.5	TSL:1	c.1174G>A	p.Glu392Lys	missense	Exon 7 of 9	ENSP00000425472.1	H0Y9Y0

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.078	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.039	T
Eigen	Benign	0.029
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	M
PhyloP100		5.4
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.086
Sift	Benign	0.070	T
Sift4G	Benign	0.46	T
Polyphen		0.044	B
Vest4		0.51
MutPred		0.46		Gain of ubiquitination at E472 (P = 0.0128)
MVP		0.37
MPC		0.16
ClinPred		0.46	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.087
gMVP		0.63
Mutation Taster		=86/14	polymorphism

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

Other links and lift over

hg19: chr4-15627311;