2-73260845-G-T

Variant names:

• chr2-73260845-G-T
• rs1239912088
• NM_001371389.2:c.2185C>A

Variant summary

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

The NM_001371389.2(FBXO41):​c.2185C>A​(p.Arg729Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000425 in 1,410,834 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R729H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: FBXO41 NM_001371389.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.21

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, 0.773

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXO41	NM_001371389.2	c.2185C>A	p.Arg729Ser	missense_variant	Exon 10 of 13	ENST00000520530.3	NP_001358318.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBXO41	ENST00000520530.3	c.2185C>A	p.Arg729Ser	missense_variant	Exon 10 of 13	5	NM_001371389.2	ENSP00000430968.2
FBXO41	ENST00000295133.9	c.2185C>A	p.Arg729Ser	missense_variant	Exon 9 of 12	1		ENSP00000295133.6
FBXO41	ENST00000521871.5	c.2185C>A	p.Arg729Ser	missense_variant	Exon 10 of 13	5		ENSP00000428646.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000425 AC: 6 AN: 1410834 Hom.: 0 Cov.: 31 AF XY: 0.00000574 AC XY: 4 AN XY: 696848

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000553

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

Feb 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2185C>A (p.R729S) alteration is located in exon 9 (coding exon 9) of the FBXO41 gene. This alteration results from a C to A substitution at nucleotide position 2185, causing the arginine (R) at amino acid position 729 to be replaced by a serine (S). 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	0.99
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.012	T;T;T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D;.;.
M_CAP	Benign	0.016	T
MetaRNN	Pathogenic	0.77	D;D;D
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	1.7	L;L;L
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-2.2	.;N;.
REVEL	Benign	0.27
Sift	Uncertain	0.023	.;D;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.99	D;D;D
Vest4		0.89
MutPred		0.54		Loss of MoRF binding (P = 0.0131);Loss of MoRF binding (P = 0.0131);Loss of MoRF binding (P = 0.0131);
MVP		0.61
MPC		0.62
ClinPred		0.91	D
GERP RS		4.8
Varity_R		0.47
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1239912088; hg19: chr2-73487973;