rs200365973
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_002972.4(SBF1):c.2605G>A(p.Val869Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000406 in 1,613,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00033 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00041 ( 0 hom. )
Consequence
SBF1
NM_002972.4 missense
NM_002972.4 missense
Scores
6
9
3
Clinical Significance
Conservation
PhyloP100: 7.79
Genes affected
SBF1 (HGNC:10542): (SET binding factor 1) This gene encodes a member of the protein-tyrosine phosphatase family. However, the encoded protein does not appear to be a catalytically active phosphatase because it lacks several amino acids in the catalytic pocket. This protein contains a Guanine nucleotide exchange factor (GEF) domain which is necessary for its role in growth and differentiation. Mutations in this gene have been associated with Charcot-Marie-Tooth disease 4B3. Pseudogenes of this gene have been defined on chromosomes 1 and 8. [provided by RefSeq, Dec 2014]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.759
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SBF1 | NM_002972.4 | c.2605G>A | p.Val869Met | missense_variant | 21/41 | ENST00000380817.8 | |
SBF1 | NM_001410794.1 | c.2608G>A | p.Val870Met | missense_variant | 21/41 | ||
SBF1 | NM_001365819.1 | c.2608G>A | p.Val870Met | missense_variant | 21/40 | ||
SBF1 | NM_001410795.1 | c.2605G>A | p.Val869Met | missense_variant | 21/40 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SBF1 | ENST00000380817.8 | c.2605G>A | p.Val869Met | missense_variant | 21/41 | 1 | NM_002972.4 | P3 |
Frequencies
GnomAD3 genomes AF: 0.000335 AC: 51AN: 152258Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000225 AC: 56AN: 248848Hom.: 0 AF XY: 0.000274 AC XY: 37AN XY: 135216
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GnomAD4 exome AF: 0.000413 AC: 604AN: 1461402Hom.: 0 Cov.: 34 AF XY: 0.000389 AC XY: 283AN XY: 727004
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GnomAD4 genome AF: 0.000335 AC: 51AN: 152258Hom.: 0 Cov.: 33 AF XY: 0.000323 AC XY: 24AN XY: 74388
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 20, 2022 | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 869 of the SBF1 protein (p.Val869Met). This variant is present in population databases (rs200365973, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with SBF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 374671). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SBF1 protein function. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2016 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 15, 2021 | The c.2605G>A (p.V869M) alteration is located in exon 21 (coding exon 21) of the SBF1 gene. This alteration results from a G to A substitution at nucleotide position 2605, causing the valine (V) at amino acid position 869 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Charcot-Marie-Tooth disease type 4B3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;.
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D
REVEL
Uncertain
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Vest4
MVP
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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