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
SF3B1
Final classification
VUS
SF3B1 c.1986C>A · p.His662Gln
SF3B1
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 ↗
Gene diagram
· NM_012433.4 · variants mapped to exon structure
SF3B1
NM_012433.4
Fetching transcript structure from UCSC…
Applied criteria · 1 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
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