About SF3B1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
SF3B1 c.1873C>T, p.(Arg625Cys)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 3
Benign evidence criteria: 0
Pathogenic criteria applied · 3
PM1Moderate
PM1 · moderate
This missense variant affects Arg625, a recurrent SF3B1 hotspot reported across multiple studies, and published functional work on SF3B1 hotspot mutations shows abnormal 3' splice-site selection, supporting that this residue lies in a mutational hotspot and functionally important region.
PM2Supporting
PM2 · supporting
Population frequency is below the PM2 threshold of 0.1%. In gnomAD v2.1 this variant was seen in 1/251128 alleles (AF 3.98203e-06; 0.00040%), and in gnomAD v4.1 in 3/1613820 alleles (AF 1.85894e-06; 0.00019%), with no homozygotes observed.
PP3Supporting
PP3 · supporting
Multiple computational findings support a deleterious missense effect. REVEL is 0.823 and BayesDel is 0.321224, both consistent with a damaging protein effect, while SpliceAI shows no meaningful splice disruption (max delta score 0.03), which does not offset the missense prediction signal.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM1 moderate, PM2 supporting, PP3 supporting; combination = 1 moderate + 2 supporting, which maps to VUS.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
3 / 1,613,820 alleles
gnomAD v4.1: 3 / 1,613,820 alleles. Recorded AF 1.85894e-06. Recorded homozygote count 0.
gnomAD v2.1
This 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).
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; curated oncogenicity label: Likely Oncogenic.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
Cancer Hotspots
This variant lies in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
28 criteria with recorded statuses: 3 met · 5 not met · 12 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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.
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.
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.
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.
No criteria match.
Met · 3
PM1 ModerateThis missense variant affects Arg625, a recurrent SF3B1 hotspot reported across multiple studies, and published functional work on SF3B1 hotspot mutations shows abnormal 3' splice-site selection, supporting that this residue lies in a mutational hotspot and functionally important region. Details ▾Hide ▴
Evidence considered
- Codon 625 recurrence reported in uveal melanoma and other malignancies
- SF3B1 hotspot mutations induce aberrant splicing
Still missing
- Variant-level hotspot database parsing was flagged for human review.
Sources
PM2 SupportingPopulation frequency is below the PM2 threshold of 0.1%. In gnomAD v2.1 this variant was seen in 1/251128 alleles (AF 3.98203e-06; 0.00040%), and in gnomAD v4.1 in 3/1613820 alleles (AF 1.85894e-06; 0.00019%), with no homozygotes observed. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF 3.98203e-06
- gnomAD v4.1 AF 1.85894e-06
Sources
PP3 SupportingMultiple computational findings support a deleterious missense effect. REVEL is 0.823 and BayesDel is 0.321224, both consistent with a damaging protein effect, while SpliceAI shows no meaningful splice disruption (max delta score 0.03), which does not offset the missense prediction signal. Details ▾Hide ▴
Evidence considered
- REVEL 0.823
- BayesDel 0.321224
- SpliceAI max delta 0.03
Sources
Not met · 5 · evaluated, threshold not reached
PS4 This variant has been reported in somatic cancers and is present in ClinVar, but no germline case-control dataset or statistically increased prevalence in affected individuals versus controls was identified, so PS4 is not met. Details ▾Hide ▴
Evidence considered
- Repeated somatic observations
- ClinVar record present without extractable submission details
Still missing
- No germline enrichment or odds-ratio data were identified.
Sources
BA1 Population frequency is well below the BA1 threshold of 1.0%. The highest observed overall frequency was 1.85894e-06 (0.00019%) in gnomAD v4.1. Details ▾Hide ▴
BS1 Population frequency is below the BS1 threshold of 0.3%. The highest observed subgroup frequency was 8.81228e-06 (0.00088%) in gnomAD v2.1 European non-Finnish and 2.54257e-06 (0.00025%) in gnomAD v4.1 European non-Finnish. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 NFE AF 8.81228e-06
- gnomAD v4.1 NFE AF 2.54257e-06
Sources
BS3 Available functional evidence does not support normal protein function. Published studies instead show that SF3B1 hotspot mutations are associated with abnormal splicing, and no well-established assay demonstrating a normal result for p.Arg625Cys was identified. Details ▾Hide ▴
Evidence considered
- Hotspot-mutant functional studies show abnormal splicing behavior
Still missing
- No exact-variant normal-function assay was found.
Sources
BP4 Available computational evidence does not support a benign interpretation. REVEL is 0.823 and BayesDel is 0.321224, both favoring a damaging missense effect, although SpliceAI predicts no significant splice impact with a max delta score of 0.03. Details ▾Hide ▴
Evidence considered
- REVEL 0.823
- BayesDel 0.321224
- SpliceAI max delta 0.03
Sources
Not assessed · 12 · no assessment recorded
PS1 No evidence was identified showing that this amino acid change has an established pathogenic counterpart caused by a different nucleotide substitution. Details ▾Hide ▴
Still missing
- A confirmed pathogenic alternate nucleotide change encoding p.Arg625Cys was not identified.
Sources
PS2 No de novo occurrence with confirmed maternity and paternity was identified. Details ▾Hide ▴
PS3 Published studies show that SF3B1 hotspot mutations can alter RNA splicing and downstream signaling, but the available evidence does not clearly establish a well-validated assay result for this exact p.Arg625Cys variant that is sufficient for PS3. Details ▾Hide ▴
Evidence considered
- SF3B1-mutant tumors show altered alternative splicing
- Hotspot-mutant studies support abnormal splice-site selection
Still missing
- Exact p.Arg625Cys assay-level evidence remains limited in the available materials.
- Assay validation for ACMG functional weighting was not established.
Sources
PM5 Other changes at codon 625 have been reported in cancer literature, but a clearly established pathogenic missense variant at the same residue suitable for germline PM5 application was not confirmed from the available evidence. Details ▾Hide ▴
Still missing
- A qualifying pathogenic germline missense variant at Arg625 was not confirmed.
Sources
PM6 No assumed de novo occurrence without full parental confirmation was identified. Details ▾Hide ▴
PP1 No segregation data were identified. Details ▾Hide ▴
PP2 Available evidence does not establish a gene-specific missense constraint framework suitable for PP2 application in this review. Details ▾Hide ▴
Still missing
- No qualifying gene-level PP2 framework was identified.
Sources
final_classification_framework
PP4 No patient-specific phenotype or family history was provided that would support a highly specific clinical presentation for PP4. Details ▾Hide ▴
Still missing
- Phenotype-specific clinical correlation was not available.
BS2 No evidence was identified showing this variant in healthy adult individuals in a manner sufficient for BS2. Details ▾Hide ▴
Evidence considered
- No homozygotes observed in gnomAD
Still missing
- Unaffected-carrier evidence was not identified.
Sources
BS4 No lack-of-segregation data were identified. Details ▾Hide ▴
BP2 No phase information with another pathogenic variant was identified. Details ▾Hide ▴
Still missing
- No cis/trans observation was found.
BP5 No alternate molecular diagnosis was identified that would explain a phenotype independently of this variant. Details ▾Hide ▴
Still missing
- No case-level alternate diagnosis information was available.
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AAlthough gene-level review indicates that loss of function can be relevant for SF3B1, this variant is a missense substitution and does not fall within the generic PVS1 null-variant categories of nonsense, frameshift, or canonical +/-1,2 splice-site change. Details ▾Hide ▴
Evidence considered
- Gene-level PVS1 gate marked eligible
- Variant-level PVS1 scaffold indicates non-null missense variant
Still missing
- No variant-specific null mechanism applies to this missense change.
Sources
PM3 N/ANo recessive disease context or trans observation with another pathogenic variant was identified for this variant. Details ▾Hide ▴
No further detail was recorded.
PM4 N/AThis variant is a missense substitution and does not change protein length. Details ▾Hide ▴
No further detail was recorded.
PP5 N/AA ClinVar record is present, but no submission classification or review status could be confirmed from the available data, so PP5 cannot be applied. Details ▾Hide ▴
Evidence considered
- ClinVar record present without extractable assertion details
Still missing
- No qualifying ClinVar assertion details were available.
Sources
BP1 N/ABP1 does not apply because this is a missense variant in a gene where disease-relevant missense variation is well documented. Details ▾Hide ▴
Evidence considered
- Recurrent disease-associated SF3B1 missense hotspot variation
Sources
BP3 N/AThis variant is not an in-frame deletion or insertion in a repetitive region. Details ▾Hide ▴
No further detail was recorded.
BP6 N/AA ClinVar record is present, but no supporting benign classification details or review status were available for BP6 application. Details ▾Hide ▴
Evidence considered
- ClinVar record present without extractable benign assertion details
Still missing
- No qualifying benign assertion details were available.
Sources
BP7 N/ABP7 does not apply because this is a missense variant rather than a synonymous or deep intronic change. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- SF3B1
- Transcript
- NM_012433.2
- Coding (HGVS c.)
- NM_012433.2:c.1873C>T
- Protein (HGVS p.)
- NP_036565.2:p.(Arg625Cys)
- GRCh38
- chr2:197402760 G>A
- GRCh37
- chr2:198267484 G>A
Gene diagram
Every interpreted variant in SF3B1, mapped onto the exon structure of NM_012433.2. Select a row to find it on the plot.
SF3B1NM_012433.2
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in SF3B1
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
3 / 1,613,820 alleles
AF 1.86e-06 · 0 homozygotes · FAF 6.8e-07
gnomAD v2.1
1 / 251,128 alleles
AF 3.98e-06 · 0 homozygotes
By genetic ancestry
gnomAD v4.1
AF 1.9e-06 · 3 / 1,613,820 alleles · 0 hom · FAF 6.8e-07
| European (non-Finnish)3 / 1,179,908 | 2.5e-06 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 4e-06 · 1 / 251,128 alleles · 0 hom
| European (non-Finnish)1 / 113,478 | 8.8e-06 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This 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 v2.1
This 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).
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 SupportingMultiple computational findings support a deleterious missense effect. REVEL is 0.823 and BayesDel is 0.321224, both consistent with a damaging protein effect, while SpliceAI shows no meaningful splice disruption (max delta score 0.03), which does not offset the missense prediction signal. Details ▾Hide ▴
Evidence considered
- REVEL 0.823
- BayesDel 0.321224
- SpliceAI max delta 0.03
Sources
BP4 Available computational evidence does not support a benign interpretation. REVEL is 0.823 and BayesDel is 0.321224, both favoring a damaging missense effect, although SpliceAI predicts no significant splice impact with a max delta score of 0.03. Details ▾Hide ▴
Evidence considered
- REVEL 0.823
- BayesDel 0.321224
- SpliceAI max delta 0.03
Sources
BP7 N/ABP7 does not apply because this is a missense variant rather than a synonymous or deep intronic change. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.823. BayesDel score = 0.321224.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
3 / 1,613,820 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Captured SpliceAI source record
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/3764943/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/2-198267484-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr2-197402760-G-A?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_012433.2%3Ac.1873…
- OncoKB ↗www.oncokb.org/gene/SF3B1/R625C
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=112683476
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This 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 v2.1
This 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).
ClinVar
This variant has been reported in ClinVar but submission details could not be extracted.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.823. BayesDel score = 0.321224.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV59205859, n = 105 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.