2-73260466-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

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

Scores

6
8
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.64
Variant links:
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]

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ACMG classification

Classification made for transcript

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
FBXO41NM_001371389.2 linkc.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
FBXO41ENST00000520530.3 linkc.2372G>T p.Arg791Leu missense_variant Exon 11 of 13 5 NM_001371389.2 ENSP00000430968.2 Q8TF61
FBXO41ENST00000295133.9 linkc.2372G>T p.Arg791Leu missense_variant Exon 10 of 12 1 ENSP00000295133.6 Q8TF61
FBXO41ENST00000521871.5 linkc.2372G>T p.Arg791Leu missense_variant Exon 11 of 13 5 ENSP00000428646.1 Q8TF61

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
LINK: link

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; API