22-32475043-T-G

Variant names:

• chr22-32475043-T-G
• NM_012179.4:c.41T>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_012179.4(FBXO7):​c.41T>G​(p.Leu14Arg) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L14L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FBXO7 NM_012179.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.526
• Publications: 0 publications found

Genes affected

FBXO7 (HGNC:13586): (F-box protein 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 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 and it may play a role in regulation of hematopoiesis. Alternatively spliced transcript variants of this gene have been identified with the full-length natures of only some variants being determined. [provided by RefSeq, Jul 2008]

FBXO7 Gene-Disease associations (from GenCC):

• parkinsonian-pyramidal syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.776

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012179.4. 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
	FBXO7	NM_012179.4	MANE Select	c.41T>G	p.Leu14Arg	missense	Exon 1 of 9	NP_036311.3
	FBXO7	NM_001033024.2		c.-319T>G		upstream_gene	N/A	NP_001028196.1	Q9Y3I1-2
	FBXO7	NM_001257990.2		c.-576T>G		upstream_gene	N/A	NP_001244919.1	Q9Y3I1-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXO7	ENST00000266087.12	TSL:1 MANE Select	c.41T>G	p.Leu14Arg	missense	Exon 1 of 9	ENSP00000266087.7	Q9Y3I1-1
	FBXO7	ENST00000886524.1		c.41T>G	p.Leu14Arg	missense	Exon 1 of 10	ENSP00000556583.1
	FBXO7	ENST00000920428.1		c.41T>G	p.Leu14Arg	missense	Exon 1 of 9	ENSP00000590487.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.71	T
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		0.53
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.27
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.98	D
Vest4		0.49
MutPred		0.69		Gain of disorder (P = 0.0095)
MVP		0.57
MPC		0.37
ClinPred		0.97	D
GERP RS		1.1
PromoterAI		-0.026	Neutral
Varity_R		0.66
gMVP		0.87
Mutation Taster		=66/34	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: chr22-32871030;