rs760815624
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2
The NM_205836.3(FBXO38):c.781G>A(p.Ala261Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000503 in 1,609,120 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000051 ( 0 hom. )
Consequence
FBXO38
NM_205836.3 missense
NM_205836.3 missense
Scores
6
6
7
Clinical Significance
Conservation
PhyloP100: 9.60
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 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.
BS2
High AC in GnomAd4 at 7 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FBXO38 | NM_205836.3 | c.781G>A | p.Ala261Thr | missense_variant | 7/22 | ENST00000340253.10 | NP_995308.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FBXO38 | ENST00000340253.10 | c.781G>A | p.Ala261Thr | missense_variant | 7/22 | 5 | NM_205836.3 | ENSP00000342023 | P3 |
Frequencies
GnomAD3 genomes AF: 0.0000461 AC: 7AN: 151688Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000117 AC: 29AN: 248384Hom.: 0 AF XY: 0.000134 AC XY: 18AN XY: 134346
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GnomAD4 exome AF: 0.0000508 AC: 74AN: 1457432Hom.: 0 Cov.: 32 AF XY: 0.0000455 AC XY: 33AN XY: 725066
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GnomAD4 genome AF: 0.0000461 AC: 7AN: 151688Hom.: 0 Cov.: 32 AF XY: 0.0000405 AC XY: 3AN XY: 74040
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Distal hereditary motor neuropathy type 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Mar 26, 2021 | In summary, this variant is a rare missense change with uncertain impact on protein function. Because it is found in the population at an appreciable frequency, this variant is not anticipated to cause disease. However, the available evidence is currently insufficient to prove that conclusively. 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 is present in population databases (rs760815624, ExAC 0.06%) but has not been reported in the literature in individuals with a FBXO38-related disease. This sequence change replaces alanine with threonine at codon 261 of the FBXO38 protein (p.Ala261Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
.;T;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;.
M_CAP
Benign
T
MetaRNN
Uncertain
D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Benign
N;N;N;N
MutationTaster
Benign
D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;D;D
REVEL
Uncertain
Sift
Uncertain
D;D;D;D
Sift4G
Uncertain
D;D;D;D
Polyphen
D;D;D;D
Vest4
MVP
MPC
1.6
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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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