2-73260532-C-T

Position:

• chr2-73260532-C-T

Variant summary

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

The NM_001371389.2(FBXO41):​c.2306G>A​(p.Arg769Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000624 in 1,443,210 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: FBXO41 NM_001371389.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.27

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 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
FBXO41	NM_001371389.2	c.2306G>A	p.Arg769Gln	missense_variant	11/13	ENST00000520530.3	NP_001358318.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBXO41	ENST00000520530.3	c.2306G>A	p.Arg769Gln	missense_variant	11/13	5	NM_001371389.2	ENSP00000430968.2
FBXO41	ENST00000295133.9	c.2306G>A	p.Arg769Gln	missense_variant	10/12	1		ENSP00000295133.6
FBXO41	ENST00000521871.5	c.2306G>A	p.Arg769Gln	missense_variant	11/13	5		ENSP00000428646.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000624 AC: 9 AN: 1443210 Hom.: 0 Cov.: 32 AF XY: 0.00000698 AC XY: 5 AN XY: 716194

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000259

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000725

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Jan 30, 2024

The c.2306G>A (p.R769Q) alteration is located in exon 10 (coding exon 10) of the FBXO41 gene. This alteration results from a G to A substitution at nucleotide position 2306, causing the arginine (R) at amino acid position 769 to be replaced by a glutamine (Q). 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	0.31
BayesDel_addAF	Uncertain	0.054	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0061	T;T;T
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	D;.;.
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.70	D;D;D
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	1.0	L;L;L
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.89	.;N;.
REVEL	Benign	0.25
Sift	Benign	0.19	.;T;.
Sift4G	Uncertain	0.027	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.78
MutPred		0.48		Loss of methylation at R765 (P = 0.0521);Loss of methylation at R765 (P = 0.0521);Loss of methylation at R765 (P = 0.0521);
MVP		0.52
MPC		0.35
ClinPred		0.89	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.61
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1687973863; hg19: chr2-73487660;