Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_012433.4 | MANE Select | 6463 nt | 30–3944 |
| NM_012433.2 | Alternative | 4314 nt | 49–3963 |
| NM_012433.3 | RefSeq Select | 4338 nt | 95–4009 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
Open""
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
The SF3B1 G742D variant has been functionally characterized and is associated with a damaging effect. It occurs in the HEAT domain of SF3B1, leading to abnormal recruitment of the splicing machinery to pre-mRNA, resulting in aberrant splicing of target gene transcripts. This mutation has been implicated in altered gene expression patterns in chronic lymphocytic leukemia, clustering with other SF3B1 mutations.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.03 | -54 bp |
| Donor Loss (DL) | 0.0 | 29 bp |
| Acceptor Gain (AG) | 0.01 | 27 bp |
| Donor Gain (DG) | 0.0 | 163 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to standard ACMG guidelines, the rule for PVS1 is: "Null variant in a gene where loss of function (LoF) is a known mechanism of disease (e.g., nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon deletion in a LoF gene)". The evidence for this variant shows: this is a missense variant (G742D) and not a null variant. Therefore, this criterion is not applied at Not Applied strength because the variant type is not a null variant.
PS1 (Not Applied)
According to standard ACMG guidelines, the rule for PS1 is: "Same amino acid change as a known pathogenic variant but different nucleotide change". The evidence for this variant shows: no known pathogenic variant with the same G742 amino acid change is reported. Therefore, this criterion is not applied at Not Applied strength because there is no prior pathogenic variant at this residue.
PS2 (Not Applied)
According to standard ACMG guidelines, the rule for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history". The evidence for this variant shows: no information regarding de novo occurrence is available. Therefore, this criterion is not applied at Not Applied strength because de novo status is not documented.
PS3 (Strong)
According to standard ACMG guidelines, the rule for PS3 is: "Well-established functional studies supportive of a damaging effect on the gene or gene product". The evidence for this variant shows: functional studies demonstrate that the SF3B1 G742D variant leads to abnormal recruitment of the splicing machinery and aberrant splicing of target transcripts. Therefore, this criterion is applied at Strong strength because robust in vitro and in vivo data support a damaging effect.
PS4 (Not Applied)
According to standard ACMG guidelines, the rule for PS4 is: "Prevalence in affected individuals significantly increased compared with controls". The evidence for this variant shows: no case-control prevalence data are available. Therefore, this criterion is not applied at Not Applied strength due to lack of prevalence data.
PM1 (Moderate)
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot or well-established functional domain without benign variation". The evidence for this variant shows: residue G742 resides within the HEAT domain, a known hotspot for SF3B1 mutations lacking benign variation. Therefore, this criterion is applied at Moderate strength because it resides in a critical functional domain.
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: "Absent from controls (or at extremely low frequency if recessive) in population databases". The evidence for this variant shows: not observed in gnomAD (0/226770 alleles). Therefore, this criterion is applied at Moderate strength because it is absent from large population datasets.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: "Detected in trans with a pathogenic variant for recessive disorders". The evidence for this variant shows: no data on trans occurrence for recessive inheritance. Therefore, this criterion is not applied at Not Applied strength because trans configuration data are not available.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame deletions/insertions or stop-loss variants". The evidence for this variant shows: it is a missense change without protein length alteration. Therefore, this criterion is not applied at Not Applied strength because there is no length change.
PM5 (Not Applied)
According to standard ACMG guidelines, the rule for PM5 is: "Novel missense change at an amino acid residue where a different pathogenic missense change has been seen". The evidence for this variant shows: no other pathogenic missense variants reported at residue G742. Therefore, this criterion is not applied at Not Applied strength because there is no known pathogenic variant at the same residue.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity". The evidence for this variant shows: de novo origin not assessed. Therefore, this criterion is not applied at Not Applied strength because de novo status is not documented.
PP1 (Not Applied)
According to standard ACMG guidelines, the rule for PP1 is: "Co-segregation with disease in multiple affected family members". The evidence for this variant shows: no segregation studies are available. Therefore, this criterion is not applied at Not Applied strength because family segregation data are unavailable.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease". The evidence for this variant shows: SF3B1 has both benign and pathogenic missense variants; the rate of benign missense variation is not low. Therefore, this criterion is not applied at Not Applied strength because the gene does not meet PP2 conditions.
PP3 (Not Applied)
According to standard ACMG guidelines, the rule for PP3 is: "Multiple lines of computational evidence support a deleterious effect on the gene or gene product". The evidence for this variant shows: in silico predictors are mixed (some deleterious, some benign); SpliceAI score is low (0.03). Therefore, this criterion is not applied at Not Applied strength because computational evidence is conflicting.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: "Patient’s phenotype or family history highly specific for a disease with a single genetic etiology". The evidence for this variant shows: no patient phenotype or family history details provided. Therefore, this criterion is not applied at Not Applied strength because phenotype specificity is not documented.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic, but without accessible evidence". The evidence for this variant shows: ClinVar has no entries. Therefore, this criterion is not applied at Not Applied strength because no reputable assertion exists.
BA1 (Not Applied)
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency is too high for the disorder". The evidence for this variant shows: MAF=0%. Therefore, this criterion is not applied at Not Applied strength because allele frequency is not high.
BS1 (Not Applied)
According to standard ACMG guidelines, the rule for BS1 is: "Allele frequency is greater than expected for the disorder". The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied at Not Applied strength because allele frequency is below thresholds.
BS2 (Not Applied)
According to standard ACMG guidelines, the rule for BS2 is: "Observed in healthy individuals with full penetrance expected at an early age". The evidence for this variant shows: no data on occurrence in healthy individuals. Therefore, this criterion is not applied at Not Applied strength because healthy occurrence is not documented.
BS3 (Not Applied)
According to standard ACMG guidelines, the rule for BS3 is: "Well-established functional studies show no damaging effect on protein function or splicing". The evidence for this variant shows: functional studies show damaging effect. Therefore, this criterion is not applied at Not Applied strength because functional data indicate damage.
BS4 (Not Applied)
According to standard ACMG guidelines, the rule for BS4 is: "Lack of segregation in affected family members". The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied at Not Applied strength because segregation data are absent.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene where only LoF causes disease". The evidence for this variant shows: missense is a known mechanism in SF3B1. Therefore, this criterion is not applied at Not Applied strength because missense variants are disease-causing.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant". The evidence for this variant shows: no cis/trans data. Therefore, this criterion is not applied at Not Applied strength because allelic configuration is unknown.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "In-frame deletions/insertions in a repetitive region without known function". The evidence for this variant shows: variant is a missense substitution. Therefore, this criterion is not applied at Not Applied strength because it is not an in-frame indel.
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: "Multiple lines of computational evidence suggest no impact on gene or gene product". The evidence for this variant shows: in silico predictors are mixed; SpliceAI score is low (0.03) and several tools predict benign. Therefore, this criterion is applied at Supporting strength because computational evidence leans toward no impact.
BP5 (Not Applied)
According to standard ACMG guidelines, the rule for BP5 is: "Variant found in a case with an alternate molecular basis for disease". The evidence for this variant shows: no other molecular basis reported. Therefore, this criterion is not applied at Not Applied strength because alternate basis is not identified.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign, but without accessible evidence". The evidence for this variant shows: no such reports. Therefore, this criterion is not applied at Not Applied strength because no benign assertions exist.
BP7 (Not Applied)
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous variant with no predicted impact on splicing". The evidence for this variant shows: missense change. Therefore, this criterion is not applied at Not Applied strength because the variant is not synonymous.