The SF3B1 c.1986C>A (p.His662Gln) variant has been observed in somatic cancer curation resources and has not been reported in ClinVar.1 This variant is absent from gnomAD v2.1 and is present at very low frequency in gnomAD v4.1 (7/1613874 alleles; AF 4.33739e-06; highest population AF 3.12354e-05), which is below the 0.1% rarity threshold used for PM2.2 Published studies showed that SF3B1 pathway mutations and SF3B1 disruption can alter RNA splicing, growth, and erythroid differentiation, but a well-established assay specific to p.His662Gln was not identified.3 In silico results were mixed, with REVEL 0.628 and BayesDel 0.0218, while SpliceAI predicted no significant splice impact with a maximum delta score of 0.07, so computational evidence did not support PP3 or BP4.4
Final classification
VUS
PM2
SF3B1
c.1986C>A
p.His662Gln
This variant
The SF3B1 c.1986C>A (p.His662Gln) variant has been observed in somatic cancer curation resources and has not been reported in ClinVar.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting; combination = 1 supporting, which maps to VUS.
Classification rationale
PM2
VUS
SF3B1 c.1986C>A
PM2
→
VUS
4
revelbayesdelspliceai ↗
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_012433.4 · variants mapped to exon structure
SF3B1
NM_012433.4
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 19 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 1
Strength
Supporting
Moderate
Strong
Very strong
PM2
supporting
review
Pathogenic
This variant is absent from gnomAD v2.1 and present at very low frequency in gnomAD v4.1 (7/1613874 alleles; AF 4.33739e-06; highest population AF 3.12354e-05 in Finnish individuals; grpmax FAF 6.8e-07), which is below the 0.1% rarity threshold and supports PM2.
gnomAD v2.1: 0/251370 allelesgnomAD v4.1: 7/1613874 allelesAF 4.33739e-06
Assessed · not applied
· 6 not met · 13 not assessed
Pathogenic
PS1
No pathogenic or likely pathogenic comparator producing the same amino acid change was identified in the available sources, so PS1 could not be established.
PS2
No confirmed de novo occurrence with established maternity and paternity was identified for this variant.
PS3
Published studies showed that SF3B1 pathway mutations and SF3B1 disruption can alter RNA splicing and hematopoietic function, but no well-established functional assay specific to p.(His662Gln) demonstrating a damaging effect was identified.
PS4
This variant has been observed in somatic cancer resources and is absent from ClinVar, but no germline case-control study or affected-individual enrichment dataset for this exact variant was identified, so PS4 is not met.
PM1
Available hotspot review did not confirm that p.(His662Gln) lies in a statistically significant hotspot or a well-established critical region without benign variation, so PM1 is not met.
PM6
No assumed de novo occurrence without parental confirmation was identified for this variant.
PP1
No segregation data were identified for this variant in affected family members.
PP2
Available evidence did not establish a gene-specific missense-constraint rule suitable to apply PP2 for this variant.
PP3
Computational evidence is not sufficiently concordant to support PP3.
PP4
No phenotype-specific clinical information was provided to determine whether the presentation is highly specific for an SF3B1-related disorder.
Benign
BA1
Population frequency does not meet the benign stand-alone threshold.
BS1
Population frequency does not meet the benign strong threshold.
BS2
Available population data do not establish observation of this variant in healthy individuals in a manner sufficient to apply BS2.
BS3
Published studies showed functional consequences of SF3B1 disruption and broader SF3B1 pathway mutations, but no well-established assay specific to p.(His662Gln) demonstrating normal function was identified.
BS4
No informative family data were identified showing lack of segregation with disease.
BP2
No phase data or alternate molecular diagnosis information were identified to support BP2.
BP3
No evidence was identified that this missense change lies in a repetitive region without known function.
BP4
Computational evidence does not support a benign interpretation.
BP5
No alternate molecular cause was provided that would explain the phenotype independently of this variant.
N/A · 8
PVS1 · PM3 · PM4 · PM5 · PP5 · BP1 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 4.33739e-06; MAF= 0.00043%, 7/1613874 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 3.12354e-05; MAF= 0.00312%, 2/64030 alleles, homozygotes = 0); grpmax FAF= 6.8e-07.
v2.1
This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/251370 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/16254 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00043%
· 7 / 1,613,874
0 hom · FAF 6.8e-05%
0 hom · FAF 6.8e-05%
European (Finnish) 2 / 64,030 |
0.0031% |
African/African American 1 / 74,916 |
0.0013% |
South Asian 1 / 91,086 |
0.0011% |
European (non-Finnish) 3 / 1,179,872 |
0.00025% |
+ 6 not observed (Remaining individuals, Admixed American, Amish, East Asian, Middle Eastern, Ashkenazi Jewish)
gnomAD v2.1
Absent
· 0 / 251,370
0 hom
0 hom
Not observed in any ancestry group.
+ 8 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07). REVEL score = 0.628. BayesDel score = 0.0218.
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV59205547, n = 26 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 2 PMIDs not cited in assessment
25428262 ↗
Disruption of SF3B1 results in deregulated expression and splicing of key genes and pathways in myelodysplastic syndrome hematopoietic stem and progenitor cells.
ONCOKB