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LYFE SCIENCES
Project: HERA
NM_012433.4:c.1986C>A
p.His662Gln  ·  SF3B1
ACMG/AMP
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Legacy Engine
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Classification rationale
1

The SF3B1 c.1986C>A (p.His662Gln) variant has been observed in somatic cancer curation resources and has not been reported in ClinVar.

oncokb ↗ clinvar ↗
2

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.

gnomad_v2 ↗ gnomad_v4 ↗
3

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.

PMID:21909114 ↗ PMID:25428262 ↗ oncokb ↗
4

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.

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
  • —
Gaps remaining
  • —
Rule
—
Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1This 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).
gnomAD v4.1This 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.
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 no significant splice impact for this variant (max delta score = 0.07). REVEL score = 0.628. BayesDel score = 0.0218.
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; COSV59205547, n = 26 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueH662
Hotspots ↗