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
SF3B1
Final classification
VUS
SF3B1 c.1866G>T · p.Glu622Asp
SF3B1
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 ↗
Gene diagram
· NM_012433.2 · variants mapped to exon structure
SF3B1
NM_012433.2
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= 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