19-38948646-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_024907.7(FBXO17):​c.382G>A​(p.Gly128Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000112 in 1,613,970 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 0.000046 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

FBXO17
NM_024907.7 missense

Scores

5
8
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.86
Variant links:
Genes affected
FBXO17 (HGNC:18754): (F-box protein 17) This gene encodes a member of the F-box protein family which is characterized by the F-box motif. The F-box proteins constitute one of the four subunits of the ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbxs class and it contains an F-box domain. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.97

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FBXO17NM_024907.7 linkc.382G>A p.Gly128Arg missense_variant Exon 3 of 6 ENST00000292852.9 NP_079183.4 Q96EF6
FBXO17NM_148169.3 linkc.409G>A p.Gly137Arg missense_variant Exon 3 of 6 NP_680474.1 Q96EF6
FBXO17NR_104026.2 linkn.556G>A non_coding_transcript_exon_variant Exon 3 of 6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FBXO17ENST00000292852.9 linkc.382G>A p.Gly128Arg missense_variant Exon 3 of 6 1 NM_024907.7 ENSP00000292852.3 Q96EF6
ENSG00000269547ENST00000599996.1 linkc.94G>A p.Gly32Arg missense_variant Exon 2 of 20 2 ENSP00000472465.1 M0R2C6

Frequencies

GnomAD3 genomes
AF:
0.0000460
AC:
7
AN:
152150
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000966
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:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000159
AC:
4
AN:
251196
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135770
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000579
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:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000752
AC:
11
AN:
1461820
Hom.:
0
Cov.:
31
AF XY:
0.00000825
AC XY:
6
AN XY:
727216
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000630
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000460
AC:
7
AN:
152150
Hom.:
0
Cov.:
33
AF XY:
0.0000673
AC XY:
5
AN XY:
74316
show subpopulations
Gnomad4 AFR
AF:
0.0000966
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:
0.0000441
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000264
ExAC
AF:
0.0000247
AC:
3
EpiCase
AF:
0.000164
EpiControl
AF:
0.00

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jan 31, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.409G>A (p.G137R) alteration is located in exon 3 (coding exon 3) of the FBXO17 gene. This alteration results from a G to A substitution at nucleotide position 409, causing the glycine (G) at amino acid position 137 to be replaced by an arginine (R). 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
0.83
BayesDel_addAF
Uncertain
0.090
D
BayesDel_noAF
Uncertain
0.070
CADD
Uncertain
25
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.25
T;T
Eigen
Uncertain
0.56
Eigen_PC
Uncertain
0.46
FATHMM_MKL
Benign
0.19
N
M_CAP
Uncertain
0.12
D
MetaRNN
Pathogenic
0.97
D;D
MetaSVM
Uncertain
-0.11
T
MutationAssessor
Pathogenic
3.1
M;M
PROVEAN
Pathogenic
-6.3
D;.
REVEL
Uncertain
0.45
Sift
Uncertain
0.0080
D;.
Sift4G
Benign
0.090
T;T
Polyphen
1.0
D;D
Vest4
0.87
MutPred
0.84
Gain of solvent accessibility (P = 0.0037);Gain of solvent accessibility (P = 0.0037);
MVP
0.66
MPC
1.2
ClinPred
0.90
D
GERP RS
4.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.19
gMVP
0.50

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

LitVar

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

Other links and lift over

dbSNP: rs199622732; hg19: chr19-39439286; API