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LYFE SCIENCES
Project: HERA
NM_012433.2:c.1873C>T
p.Arg625Cys  ·  SF3B1
ACMG/AMP
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Classification rationale
1

The SF3B1 c.1873C>T (p.Arg625Cys; p.R625C) variant has been observed repeatedly in somatic cancers and is recorded in ClinVar, while published studies identify codon 625 as a recurrently mutated SF3B1 hotspot.

clinvar ↗ PMID:23313955 ↗ PMID:23861464 ↗ PMID:24434863 ↗ PMID:26565915 ↗
2

This variant is rare in population databases, with 1/251128 alleles in gnomAD v2.1 (AF 3.98203e-06; 0.00040%) and 3/1613820 alleles in gnomAD v4.1 (AF 1.85894e-06; 0.00019%), both below the 0.1% PM2 threshold.

gnomad_v2 ↗ gnomad_v4 ↗
3

In published functional studies, SF3B1 hotspot-mutant tumors and model systems showed altered alternative splicing and abnormal 3' splice-site selection, supporting functional importance of the codon 625 region, although exact p.Arg625Cys assay-level evidence remains limited.

PMID:23861464 ↗ PMID:24434863 ↗ PMID:26565915 ↗ PMID:33031100 ↗
4

Computational evidence supports a deleterious missense effect, with REVEL 0.823 and BayesDel 0.321224, while SpliceAI predicts no significant splice disruption with a maximum delta score of 0.03.

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
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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= 3.98203e-06; MAF= 0.00040%, 1/251128 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.81228e-06; MAF= 0.00088%, 1/113478 alleles, homozygotes = 0).
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 1.85894e-06; MAF= 0.00019%, 3/1613820 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.54257e-06; MAF= 0.00025%, 3/1179908 alleles, homozygotes = 0); grpmax FAF= 6.8e-07.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar but submission details could not be extracted.
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 = 0.03). REVEL score = 0.823. BayesDel score = 0.321224.
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV59205859, n = 105 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant lies in a statistically significant hotspot.
ResidueR625
Hotspots ↗