The SF3B1 NM_012433.2:c.1986C>A (NP_036565.2:p.(His662Gln), p.(H662Q)) 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 remains very rare in gnomAD v4.1 at 7/1613874 alleles (0.00043%), with the highest observed population frequency of 0.00312% in Finnish individuals, which is below the 0.1% PM2 rarity threshold.2 Published SF3B1 functional literature was identified for review, but the available evidence did not provide a validated assay directly testing p.(His662Gln), so functional criteria were not applied.3 Computational evidence supports a deleterious missense effect, with REVEL 0.628 and BayesDel 0.0218, while SpliceAI shows a low maximum delta score of 0.07 and does not support a splice-altering effect.4
Final classification
VUS
PM2PP3
SF3B1
c.1986C>A
p.His662Gln
This variant
The SF3B1 NM_012433.2:c.1986C>A (NP_036565.2:p.(His662Gln), p.(H662Q)) 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 moderate, PP3 supporting; combination = 1 moderate + 1 supporting, which maps to VUS.
Classification rationale
PM2PP3
VUS
SF3B1 c.1986C>A
PM2 + PP3
→
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_012433.2 · variants mapped to exon structure
SF3B1
NM_012433.2
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 22 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 · 2
Strength
Supporting
Moderate
Strong
Very strong
PM2
moderate
review
Pathogenic
This variant is absent from gnomAD v2.1 (0/251370 alleles, 0.00000%) and is present at very low frequency in gnomAD v4.1 (7/1613874 alleles, 0.00043%; highest population frequency 0.00312% in Finnish individuals), which is below the 0.1% PM2 threshold and supports rarity.
gnomAD v2.1 total AF 0.0gnomAD v4.1 total AF 4.337389412060669e-06Finnish AF 3.123535842573794e-05
PP3
supporting
review
Pathogenic
Multiple computational predictors support a deleterious missense effect: REVEL is 0.628, above a supportive threshold of 0.6, and BayesDel is 0.0218, above 0; SpliceAI shows a maximum delta score of 0.07, below 0.2, which does not support a splice effect but does not negate protein-level deleterious prediction.
REVEL score 0.628BayesDel score 0.0218SpliceAI max delta score 0.07
Assessed · not applied
· 5 not met · 17 not assessed
Pathogenic
PS1
No evidence was identified that another nucleotide change produces the same amino acid substitution with an established pathogenic classification, so PS1 was not assessed.
PS2
No confirmed de novo occurrence with parental testing was identified for this variant, so PS2 was not assessed.
PS3
Published functional literature relevant to SF3B1 was identified, but the available evidence did not provide a validated functional assay directly testing p.(His662Gln), so PS3 was not applied.
PS4
This variant has been observed in somatic cancer resources, but no germline case-control or affected-versus-control enrichment data for p.(His662Gln) were identified, so PS4 is not met.
PM1
Available evidence does not support that this variant lies in a statistically established mutational hotspot or a well-defined critical functional domain without benign variation, so PM1 is not met.
PM3
No evidence was identified that this variant was observed in trans with a pathogenic variant in a recessive disorder context, so PM3 was not assessed.
PM5
No evidence was identified that a different missense change at codon 662 has an established pathogenic classification, so PM5 was not assessed.
PM6
No assumed de novo occurrence without full parental confirmation was identified for this variant, so PM6 was not assessed.
PP1
No segregation data were identified for this variant in affected family members, so PP1 was not assessed.
PP2
Available evidence does not establish a gene-specific missense-constraint rule for SF3B1 that would justify PP2, so this criterion was not assessed.
PP4
No patient phenotype or disease-specific clinical presentation was provided that is highly specific for a single-gene disorder caused by SF3B1, so PP4 was not assessed.
PP5
No germline reputable-source pathogenic classification for this variant was identified, so PP5 was not assessed.
Benign
BA1
The highest observed population frequency is 0.00312% in gnomAD v4.1, which is well below the 1% BA1 threshold, so BA1 is not met.
BS1
The highest observed population frequency is 0.00312% in gnomAD v4.1, which is below the 0.3% BS1 threshold, so BS1 is not met.
BS2
This variant is very rare in population databases and no evidence was identified showing occurrence in healthy adults at a frequency sufficient for BS2, so BS2 was not assessed.
BS3
No well-established functional study was identified showing normal function for p.(His662Gln), so BS3 was not applied.
BS4
No non-segregation data were identified for this variant in affected families, so BS4 was not assessed.
BP2
No evidence was identified that this variant occurs in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant, so BP2 was not assessed.
BP3
No evidence was identified that this variant lies in a repetitive region without known function, so BP3 was not assessed.
BP4
Available computational evidence does not support a benign effect: REVEL is 0.628 and BayesDel is 0.0218, both consistent with deleterious missense prediction, while SpliceAI is 0.07 and only argues against a splice effect.
BP5
No alternate molecular diagnosis or independent cause for disease was provided, so BP5 was not assessed.
BP6
No reputable benign classification for this variant was identified, so BP6 was not assessed.
N/A · 4
PVS1 · PM4 · BP1 · 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