2-73260466-C-A

Variant names:

• chr2-73260466-C-A
• NM_001371389.2:c.2372G>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001371389.2(FBXO41):​c.2372G>T​(p.Arg791Leu) variant causes a missense change. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R791Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBXO41 NM_001371389.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.64

Genes affected

FBXO41 (HGNC:29409): (F-box protein 41) This gene encodes a member of the F-box protein family, which is characterized by an approximately 40 amino acid motif, the F-box. F-box proteins constitute one of the four subunits of the SCF ubiquitin protein ligase complex that plays a role in phosphorylation-dependent ubiquitination. F-box proteins are divided into three classes depending on the interaction substrate domain each contains in addition to the F-box motif: FBXW proteins contain WD-40 domains, FBXL proteins contain leucine-rich repeats, and FBXO proteins contain either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the FBXO class. [provided by RefSeq, Feb 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.837

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXO41	NM_001371389.2	c.2372G>T	p.Arg791Leu	missense_variant	Exon 11 of 13	ENST00000520530.3	NP_001358318.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBXO41	ENST00000520530.3	c.2372G>T	p.Arg791Leu	missense_variant	Exon 11 of 13	5	NM_001371389.2	ENSP00000430968.2
FBXO41	ENST00000295133.9	c.2372G>T	p.Arg791Leu	missense_variant	Exon 10 of 12	1		ENSP00000295133.6
FBXO41	ENST00000521871.5	c.2372G>T	p.Arg791Leu	missense_variant	Exon 11 of 13	5		ENSP00000428646.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 30, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2372G>T (p.R791L) alteration is located in exon 10 (coding exon 10) of the FBXO41 gene. This alteration results from a G to T substitution at nucleotide position 2372, causing the arginine (R) at amino acid position 791 to be replaced by a leucine (L). 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	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;T;T
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.95	D;.;.
M_CAP	Benign	0.040	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.7	L;L;L
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.1	.;D;.
REVEL	Uncertain	0.36
Sift	Uncertain	0.0040	.;D;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.99	D;D;D
Vest4		0.94
MutPred		0.46		Gain of catalytic residue at R791 (P = 0.0479);Gain of catalytic residue at R791 (P = 0.0479);Gain of catalytic residue at R791 (P = 0.0479);
MVP		0.81
MPC		0.61
ClinPred		0.99	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.67
gMVP		0.65

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-73487594;