rs371555180

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBP6BS2

The NM_205836.3(FBXO38):ā€‹c.2889G>Cā€‹(p.Lys963Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000402 in 1,613,804 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.00037 ( 0 hom., cov: 32)
Exomes š‘“: 0.00041 ( 0 hom. )

Consequence

FBXO38
NM_205836.3 missense

Scores

1
5
13

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 1.19
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FBXO38. . Gene score misZ 2.8126 (greater than the threshold 3.09). Trascript score misZ 3.83 (greater than threshold 3.09). GenCC has associacion of gene with distal hereditary motor neuropathy type 2, neuronopathy, distal hereditary motor, type 2D, distal hereditary motor neuropathy.
BP4
Computational evidence support a benign effect (MetaRNN=0.07050857).
BP6
Variant 5-148438363-G-C is Benign according to our data. Variant chr5-148438363-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 581512.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
BS2
High AC in GnomAd4 at 57 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
FBXO38NM_205836.3 linkuse as main transcriptc.2889G>C p.Lys963Asn missense_variant 18/22 ENST00000340253.10 NP_995308.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FBXO38ENST00000340253.10 linkuse as main transcriptc.2889G>C p.Lys963Asn missense_variant 18/225 NM_205836.3 ENSP00000342023.6 Q6PIJ6-1

Frequencies

GnomAD3 genomes
AF:
0.000375
AC:
57
AN:
152064
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000169
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00118
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:
0.000470
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000223
AC:
56
AN:
251108
Hom.:
0
AF XY:
0.000236
AC XY:
32
AN XY:
135704
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.000289
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:
0.000379
Gnomad OTH exome
AF:
0.000327
GnomAD4 exome
AF:
0.000405
AC:
592
AN:
1461620
Hom.:
0
Cov.:
31
AF XY:
0.000408
AC XY:
297
AN XY:
727110
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.000496
Gnomad4 OTH exome
AF:
0.000447
GnomAD4 genome
AF:
0.000375
AC:
57
AN:
152184
Hom.:
0
Cov.:
32
AF XY:
0.000376
AC XY:
28
AN XY:
74392
show subpopulations
Gnomad4 AFR
AF:
0.000169
Gnomad4 AMR
AF:
0.00118
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000471
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000357
Hom.:
0
Bravo
AF:
0.000344
TwinsUK
AF:
0.000809
AC:
3
ALSPAC
AF:
0.000778
AC:
3
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.000189
AC:
23
EpiCase
AF:
0.000491
EpiControl
AF:
0.000534

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJun 08, 2022In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015) -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsMar 04, 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
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 28, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.50
BayesDel_addAF
Benign
-0.34
T
BayesDel_noAF
Benign
-0.41
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.21
.;T;.;.
Eigen
Benign
-0.16
Eigen_PC
Benign
-0.10
FATHMM_MKL
Uncertain
0.84
D
LIST_S2
Uncertain
0.95
D;D;D;.
M_CAP
Benign
0.012
T
MetaRNN
Benign
0.071
T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.81
.;L;.;.
PrimateAI
Pathogenic
0.86
D
PROVEAN
Uncertain
-2.8
D;N;D;D
REVEL
Benign
0.095
Sift
Benign
0.091
T;D;D;T
Sift4G
Benign
0.068
T;T;T;T
Polyphen
0.56
P;D;P;P
Vest4
0.54
MutPred
0.33
.;Loss of sheet (P = 0.0181);.;.;
MVP
0.093
MPC
1.2
ClinPred
0.075
T
GERP RS
1.7
Varity_R
0.36
gMVP
0.60

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: rs371555180; hg19: chr5-147817926; API