2-73263977-C-A

Variant summary

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

The NM_001371389.2(FBXO41):​c.1883G>T​(p.Gly628Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000224 in 1,606,758 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 (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

FBXO41
NM_001371389.2 missense

Scores

3
10
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.69
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]

Genome browser will be placed here

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, 0.768

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FBXO41NM_001371389.2 linkc.1883G>T p.Gly628Val missense_variant Exon 7 of 13 ENST00000520530.3 NP_001358318.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FBXO41ENST00000520530.3 linkc.1883G>T p.Gly628Val missense_variant Exon 7 of 13 5 NM_001371389.2 ENSP00000430968.2 Q8TF61
FBXO41ENST00000295133.9 linkc.1883G>T p.Gly628Val missense_variant Exon 6 of 12 1 ENSP00000295133.6 Q8TF61
FBXO41ENST00000521871.5 linkc.1883G>T p.Gly628Val missense_variant Exon 7 of 13 5 ENSP00000428646.1 Q8TF61

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152252
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000482
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000855
AC:
2
AN:
233916
Hom.:
0
AF XY:
0.0000157
AC XY:
2
AN XY:
127002
show subpopulations
Gnomad AFR exome
AF:
0.0000735
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000951
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000227
AC:
33
AN:
1454506
Hom.:
0
Cov.:
33
AF XY:
0.0000208
AC XY:
15
AN XY:
722888
show subpopulations
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:
0.0000298
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152252
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74392
show subpopulations
Gnomad4 AFR
AF:
0.0000482
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000277
Hom.:
0
ExAC
AF:
0.00000828
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Dec 12, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1883G>T (p.G628V) alteration is located in exon 6 (coding exon 6) of the FBXO41 gene. This alteration results from a G to T substitution at nucleotide position 1883, causing the glycine (G) at amino acid position 628 to be replaced by a valine (V). 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
Uncertain
0.43
BayesDel_addAF
Uncertain
0.091
D
BayesDel_noAF
Uncertain
0.080
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Benign
0.39
T;T;T
Eigen
Uncertain
0.49
Eigen_PC
Uncertain
0.53
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.90
D;.;.
M_CAP
Benign
0.018
T
MetaRNN
Pathogenic
0.77
D;D;D
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.6
L;L;L
PrimateAI
Pathogenic
0.87
D
PROVEAN
Uncertain
-3.1
.;D;.
REVEL
Uncertain
0.30
Sift
Benign
0.071
.;T;.
Sift4G
Uncertain
0.045
D;D;D
Polyphen
1.0
D;D;D
Vest4
0.93
MutPred
0.26
Loss of catalytic residue at P624 (P = 0.0914);Loss of catalytic residue at P624 (P = 0.0914);Loss of catalytic residue at P624 (P = 0.0914);
MVP
0.41
MPC
1.1
ClinPred
0.86
D
GERP RS
5.1
Varity_R
0.56
gMVP
0.63

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs778503960; hg19: chr2-73491105; API