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LYFE SCIENCES
Project: HERA
NM_012433.2:c.1866G>T
p.Glu622Asp  ·  SF3B1
ACMG/AMP
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Classification rationale
1

The SF3B1 c.1866G>T (p.Glu622Asp; p.E622D) variant has been observed in somatic cancer resources and has not been reported in ClinVar.

oncokb ↗ clinvar ↗
2

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%.

gnomad_v2 ↗ gnomad_v4 ↗
3

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.

PMID:21909114 ↗ PMID:25428262 ↗
4

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.

spliceai ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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Rationale
Select a criterion to inspect its explanation.
Evidence used
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Gaps remaining
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Rule
—
Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1Absent from gnomAD v2.1.
gnomAD v4.1This 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.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant is absent from ClinVar.
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; curated oncogenicity label: Likely Oncogenic.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.27). REVEL score = 0.455. BayesDel score = -0.0897007.
SpliceAI ↗
COSMIC evidence
05
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).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueE622
Hotspots ↗