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rs200187682

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2BP4_StrongBP6_Very_StrongBS2

The NM_205836.3(FBXO38):c.1394G>A(p.Arg465His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000141 in 1,598,280 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

FBXO38
NM_205836.3 missense

Scores

7
5
6

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 7.77
Variant links:
Genes affected
FBXO38 (HGNC:28844): (F-box protein 38) This gene encodes a large protein that contains an F-box domain and may participate in protein ubiquitination. The encoded protein is a transcriptional co-activator of Krueppel-like factor 7 (Klf7). A heterozygous mutation in this gene was found in individuals with autosomal dominant distal hereditary motor neuronopathy type IID. There is a pseudogene for this gene on chromosome 4. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2013]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

PP2
Missense variant where missense usually causes diseases, FBXO38
BP4
Computational evidence support a benign effect (MetaRNN=0.027974397).
BP6
Variant 5-148416057-G-A is Benign according to our data. Variant chr5-148416057-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 473948.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS2
High AC in GnomAd at 16 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
FBXO38NM_205836.3 linkuse as main transcriptc.1394G>A p.Arg465His missense_variant 11/22 ENST00000340253.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
FBXO38ENST00000340253.10 linkuse as main transcriptc.1394G>A p.Arg465His missense_variant 11/225 NM_205836.3 P3Q6PIJ6-1

Frequencies

GnomAD3 genomes
AF:
0.000105
AC:
16
AN:
151806
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00346
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000589
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000297
AC:
71
AN:
239182
Hom.:
0
AF XY:
0.000317
AC XY:
41
AN XY:
129436
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00630
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000916
Gnomad OTH exome
AF:
0.000350
GnomAD4 exome
AF:
0.000145
AC:
210
AN:
1446474
Hom.:
0
Cov.:
31
AF XY:
0.000148
AC XY:
106
AN XY:
718288
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00591
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000377
Gnomad4 NFE exome
AF:
0.0000326
Gnomad4 OTH exome
AF:
0.000335
GnomAD4 genome
AF:
0.000105
AC:
16
AN:
151806
Hom.:
0
Cov.:
32
AF XY:
0.0000944
AC XY:
7
AN XY:
74114
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00346
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000589
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000483
Hom.:
0
Bravo
AF:
0.000151
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.000296
AC:
36

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsJun 30, 2020This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Distal hereditary motor neuropathy type 2 Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeJan 02, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Benign
-0.013
T
BayesDel_noAF
Uncertain
-0.060
Cadd
Pathogenic
32
Dann
Pathogenic
1.0
Eigen
Pathogenic
0.75
Eigen_PC
Pathogenic
0.78
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.98
D;D;D;.
M_CAP
Benign
0.020
T
MetaRNN
Benign
0.028
T;T;T;T
MetaSVM
Benign
-0.80
T
MutationAssessor
Benign
0.90
L;L;L;L
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Pathogenic
0.84
D
PROVEAN
Uncertain
-3.6
D;D;D;D
REVEL
Uncertain
0.32
Sift
Uncertain
0.013
D;D;D;D
Sift4G
Uncertain
0.037
D;D;D;D
Polyphen
1.0
D;D;D;D
Vest4
0.72
MVP
0.41
MPC
1.8
ClinPred
0.16
T
GERP RS
5.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.40
gMVP
0.63

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: rs200187682; hg19: chr5-147795620; API