rs147438385
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The ENST00000256190.13(SBF2):āc.3127A>Gā(p.Ile1043Val) variant causes a missense change. The variant allele was found at a frequency of 0.000142 in 1,614,138 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 0.00017 ( 0 hom., cov: 32)
Exomes š: 0.00014 ( 0 hom. )
Consequence
SBF2
ENST00000256190.13 missense
ENST00000256190.13 missense
Scores
6
13
Clinical Significance
Conservation
PhyloP100: 3.76
Genes affected
SBF2 (HGNC:2135): (SET binding factor 2) This gene encodes a pseudophosphatase and member of the myotubularin-related protein family. This gene maps within the CMT4B2 candidate region of chromosome 11p15 and mutations in this gene have been associated with Charcot-Marie-Tooth Disease, type 4B2. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SBF2 | NM_030962.4 | c.3127A>G | p.Ile1043Val | missense_variant | 25/40 | ENST00000256190.13 | NP_112224.1 | |
LOC101928008 | NR_120539.1 | n.135+3478T>C | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SBF2 | ENST00000256190.13 | c.3127A>G | p.Ile1043Val | missense_variant | 25/40 | 1 | NM_030962.4 | ENSP00000256190 | P3 | |
ENST00000533659.1 | n.134+3478T>C | intron_variant, non_coding_transcript_variant | 1 |
Frequencies
GnomAD3 genomes AF: 0.000171 AC: 26AN: 152216Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000103 AC: 26AN: 251338Hom.: 0 AF XY: 0.000140 AC XY: 19AN XY: 135834
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GnomAD4 exome AF: 0.000139 AC: 203AN: 1461804Hom.: 0 Cov.: 31 AF XY: 0.000139 AC XY: 101AN XY: 727206
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GnomAD4 genome AF: 0.000171 AC: 26AN: 152334Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9AN XY: 74494
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Feb 01, 2023 | BP4, PM2 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Aug 30, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 11, 2017 | A variant of uncertain significance has been identified in the SBF2 gene. The c.3127 A>G variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.3127 A>G variant is observed in 13/66692 (0.02%) alleles from individuals of European background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Several in-silico splice prediction models predict that c.3127 A>G creates a cryptic acceptor site for intron 24 which may supplant the natural acceptor site and lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. If the c.3127 A>G variant does not affect splicing, it will result in the I1043V missense change. The I1043V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Isoleucine are tolerated across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. - |
Charcot-Marie-Tooth disease Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Genetics Laboratory, London Health Sciences Centre | - | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 27, 2021 | The p.I1043V variant (also known as c.3127A>G), located in coding exon 25 of the SBF2 gene, results from an A to G substitution at nucleotide position 3127. The isoleucine at codon 1043 is replaced by valine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Charcot-Marie-Tooth disease type 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 17, 2022 | This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1043 of the SBF2 protein (p.Ile1043Val). This variant is present in population databases (rs147438385, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of Charcot-Marie-Tooth disease (PMID: 32376792). ClinVar contains an entry for this variant (Variation ID: 220646). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Benign
D
MetaRNN
Benign
T
MetaSVM
Uncertain
T
MutationAssessor
Benign
L
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Benign
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
B
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: -1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at