The SF3B1 c.1866G>T (p.Glu622Asp; p.E622D) variant has been observed in somatic cancer resources and has not been reported in ClinVar.1 In population databases, this variant is absent from gnomAD v2.1 and is present at very low frequency in gnomAD v4.1 (AF 2.478382310298422e-06, 4/1613956 alleles), which is below the default PM2 threshold of 0.1%.2 Published studies show that disease-associated SF3B1 missense variants cluster in functionally important splicing regions and can disrupt RNA splicing, but no well-established functional assay specific to p.Glu622Asp was identified.3 Computational results are mixed: REVEL is 0.455, BayesDel is -0.0897007, and SpliceAI predicts a possible splice effect with a maximum delta score of 0.27, so in silico evidence does not clearly support either a damaging or benign interpretation.4
Final classification
VUS
PM2
SF3B1
c.1866G>T
p.Glu622Asp
This variant
The SF3B1 c.1866G>T (p.Glu622Asp; p.E622D) variant has been observed in somatic cancer 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; combination = 1 moderate, which maps to VUS.
Classification rationale
PM2
VUS
SF3B1 c.1866G>T
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_012433.2 · variants mapped to exon structure
SF3B1
NM_012433.2
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 21 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
moderate
review
Pathogenic
This variant is absent from gnomAD v2.1 and is present at very low frequency in gnomAD v4.1 with AF 2.478382310298422e-06 (0.00025%, 4/1613956 alleles), which is below the default PM2 threshold of 0.1%. This rarity supports PM2.
Absent from gnomAD v2.1.Present in gnomAD v4.1 at AF 2.478382310298422e-06.
Assessed · not applied
· 5 not met · 16 not assessed
Pathogenic
PS1
No evidence was identified showing that this exact amino acid change, p.Glu622Asp (p.E622D), matches a previously established pathogenic variant caused by a different nucleotide change.
PS2
No confirmed de novo occurrence with parental confirmation was identified for this variant.
PS3
Published studies show that SF3B1 alterations can disrupt splicing and cell function, but no well-established functional study specific to p.Glu622Asp was identified.
PS4
This variant has variant-specific somatic cancer context, but no germline case-control or affected-individual enrichment data were identified to show that it is significantly more common in affected individuals than in controls.
PM1
Published studies show that recurrent SF3B1 missense variants cluster in the HEAT-repeat region, but the available hotspot review did not identify p.Glu622Asp or codon 622 as a statistically significant hotspot.
PM3
No evidence was identified showing this variant in trans with a pathogenic variant in a recessive disorder.
PM5
No evidence was identified showing a different pathogenic missense change at codon 622 that would support PM5 for this novel amino acid substitution.
PM6
No assumed de novo occurrence without full parental confirmation was identified for this variant.
PP1
No segregation data were identified for this variant.
PP2
SF3B1 is known to harbor disease-relevant missense variation, but no gene-specific missense constraint rule or calibrated framework was identified here to support PP2 for this variant.
PP3
Available computational evidence is mixed rather than consistently damaging.
PP4
No phenotype information was provided that is sufficiently specific for a single-gene or narrow differential diagnosis assessment.
Benign
BA1
The observed gnomAD v4.1 allele frequency is 2.478382310298422e-06 (0.00025%), which is well below the default BA1 threshold of 1%, so BA1 is not met.
BS1
The observed gnomAD v4.1 allele frequency is 2.478382310298422e-06 (0.00025%), which is below the default BS1 threshold of 0.3%, so BS1 is not met.
BS2
This variant is rare in population databases and no evidence was identified showing observation in healthy adults in a manner sufficient to apply BS2.
BS3
No well-established functional study showing no damaging effect for p.Glu622Asp was identified.
BS4
No non-segregation evidence was identified for this variant.
BP2
No phase data were identified to show this variant occurs in cis with a pathogenic variant or in trans in a manner supporting BP2.
BP3
No evidence was identified showing that this missense change is located in a repetitive region without known function that would support BP3.
BP4
Available computational evidence does not provide a clearly benign prediction.
BP5
No evidence was identified for an alternate molecular explanation for disease that would support BP5.
N/A · 6
PVS1 · PM4 · 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= 2.47838e-06; MAF= 0.00025%, 4/1613956 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.38987e-06; MAF= 0.00034%, 4/1179986 alleles, homozygotes = 0); grpmax FAF= 7.9e-07.
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00025%
· 4 / 1,613,956
0 hom · FAF 7.9e-05%
0 hom · FAF 7.9e-05%
European (non-Finnish) 4 / 1,179,986 |
0.00034% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.27). REVEL score = 0.455. BayesDel score = -0.0897007.
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; COSV59206479, n = 43 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links