rs149713669
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2
The NM_205836.3(FBXO38):c.3362G>A(p.Arg1121Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000347 in 1,613,250 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000036 ( 0 hom. )
Consequence
FBXO38
NM_205836.3 missense
NM_205836.3 missense
Scores
4
5
8
Clinical Significance
Conservation
PhyloP100: 7.65
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 Likely_benign. Variant got -3 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, FBXO38
BS2
?
High AC in GnomAdExome at 5 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FBXO38 | NM_205836.3 | c.3362G>A | p.Arg1121Gln | missense_variant | 21/22 | ENST00000340253.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBXO38 | ENST00000340253.10 | c.3362G>A | p.Arg1121Gln | missense_variant | 21/22 | 5 | NM_205836.3 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152138Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000200 AC: 5AN: 250550Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 135418
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GnomAD4 exome AF: 0.0000363 AC: 53AN: 1461112Hom.: 0 Cov.: 30 AF XY: 0.0000316 AC XY: 23AN XY: 726854
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GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152138Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74330
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1Other:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Distal hereditary motor neuropathy type 2 Uncertain:1Other:1
not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | Variant interpreted as Uncertain significance and reported on 11-03-2017 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 23, 2021 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with FBXO38-related disease. This variant is present in population databases (rs149713669, ExAC 0.007%). This sequence change replaces arginine with glutamine at codon 1046 of the FBXO38 protein (p.Arg1046Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Pathogenic
Dann
Pathogenic
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;.
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D;D
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N
REVEL
Benign
Sift
Benign
T;D;D;T
Sift4G
Uncertain
D;D;D;D
Polyphen
D;D;D;D
Vest4
MVP
MPC
1.9
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at