rs550138374
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Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2
The NM_205836.3(FBXO38):āc.3439A>Gā(p.Met1147Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000149 in 1,614,068 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 Uncertain significance (ā ā ).
Frequency
Genomes: š 0.000026 ( 0 hom., cov: 33)
Exomes š: 0.000014 ( 0 hom. )
Consequence
FBXO38
NM_205836.3 missense
NM_205836.3 missense
Scores
3
5
11
Clinical Significance
Conservation
PhyloP100: 7.07
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 -5 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=0.13936138).
BS2
High AC in GnomAdExome4 at 20 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FBXO38 | NM_205836.3 | c.3439A>G | p.Met1147Val | missense_variant | 22/22 | ENST00000340253.10 | NP_995308.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FBXO38 | ENST00000340253.10 | c.3439A>G | p.Met1147Val | missense_variant | 22/22 | 5 | NM_205836.3 | ENSP00000342023 | P3 | |
FBXO38 | ENST00000394370.7 | c.3214A>G | p.Met1072Val | missense_variant | 22/22 | 1 | ENSP00000377895 | A1 | ||
FBXO38 | ENST00000513826.1 | c.2704A>G | p.Met902Val | missense_variant | 20/20 | 1 | ENSP00000426410 | A1 | ||
FBXO38 | ENST00000296701.10 | c.2704A>G | p.Met902Val | missense_variant | 21/21 | 2 | ENSP00000296701 | A1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152266Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000438 AC: 11AN: 251084Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135688
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GnomAD4 exome AF: 0.0000137 AC: 20AN: 1461802Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11AN XY: 727216
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152266Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74398
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
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 | Feb 14, 2023 | 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. This variant has not been reported in the literature in individuals affected with FBXO38-related conditions. This missense change has been observed in at least one individual who was not affected with FBXO38-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 576603). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). This variant is present in population databases (rs550138374, gnomAD 0.03%). This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1072 of the FBXO38 protein (p.Met1072Val). - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 30, 2023 | In 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) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
.;T;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;.
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
.;L;.;.
MutationTaster
Benign
D;D;N;N
PrimateAI
Pathogenic
T
PROVEAN
Uncertain
D;D;D;D
REVEL
Benign
Sift
Benign
T;D;D;T
Sift4G
Benign
T;T;T;T
Polyphen
B;D;P;B
Vest4
MutPred
0.25
.;Gain of sheet (P = 0.0061);.;.;
MVP
MPC
1.6
ClinPred
T
GERP RS
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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