About SF3B1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
SF3B1 c.1986C>A, p.(His662Gln)
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
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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: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM2Moderate
PM2 · moderate
This variant is absent from gnomAD v2.1 (0/251370 alleles, 0.00000%) and is present at very low frequency in gnomAD v4.1 (7/1613874 alleles, 0.00043%; highest population frequency 0.00312% in Finnish individuals), which is below the 0.1% PM2 threshold and supports rarity.
PP3Supporting
PP3 · supporting
Multiple computational predictors support a deleterious missense effect: REVEL is 0.628, above a supportive threshold of 0.6, and BayesDel is 0.0218, above 0; SpliceAI shows a maximum delta score of 0.07, below 0.2, which does not support a splice effect but does not negate protein-level deleterious prediction.
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: PM2 moderate, PP3 supporting; combination = 1 moderate + 1 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
7 / 1,613,874 alleles
gnomAD v4.1: 7 / 1,613,874 alleles. Recorded AF 4.33739e-06. Recorded homozygote count 0.
gnomAD v2.1
This 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).
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 does not lie 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: 2 met · 5 not met · 17 not assessed · 4 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 NM_012433.2:c.1986C>A (NP_036565.2:p.(His662Gln), p.(H662Q)) variant has been observed in somatic cancer curation resources and has not been reported in ClinVar.
This variant is absent from gnomAD v2.1 and remains very rare in gnomAD v4.1 at 7/1613874 alleles (0.00043%), with the highest observed population frequency of 0.00312% in Finnish individuals, which is below the 0.1% PM2 rarity threshold.
Published SF3B1 functional literature was identified for review, but the available evidence did not provide a validated assay directly testing p.(His662Gln), so functional criteria were not applied.
Computational evidence supports a deleterious missense effect, with REVEL 0.628 and BayesDel 0.0218, while SpliceAI shows a low maximum delta score of 0.07 and does not support a splice-altering effect.
No criteria match.
Met · 2
PM2 ModerateThis variant is absent from gnomAD v2.1 (0/251370 alleles, 0.00000%) and is present at very low frequency in gnomAD v4.1 (7/1613874 alleles, 0.00043%; highest population frequency 0.00312% in Finnish individuals), which is below the 0.1% PM2 threshold and supports rarity. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 total AF 0.0
- gnomAD v4.1 total AF 4.337389412060669e-06
- Finnish AF 3.123535842573794e-05
- no homozygotes
Sources
PP3 SupportingMultiple computational predictors support a deleterious missense effect: REVEL is 0.628, above a supportive threshold of 0.6, and BayesDel is 0.0218, above 0; SpliceAI shows a maximum delta score of 0.07, below 0.2, which does not support a splice effect but does not negate protein-level deleterious prediction. Details ▾Hide ▴
Evidence considered
- REVEL score 0.628
- BayesDel score 0.0218
- SpliceAI max delta score 0.07
Sources
Not met · 5 · evaluated, threshold not reached
PS4 This variant has been observed in somatic cancer resources, but no germline case-control or affected-versus-control enrichment data for p.(His662Gln) were identified, so PS4 is not met. Details ▾Hide ▴
Evidence considered
- Somatic oncology resources identified the variant context.
- ClinVar had no germline submission for this variant.
Still missing
- No germline exact-variant prevalence or odds ratio data were identified.
Sources
PM1 Available evidence does not support that this variant lies in a statistically established mutational hotspot or a well-defined critical functional domain without benign variation, so PM1 is not met. Details ▾Hide ▴
Evidence considered
- Cancer Hotspots review reported no significant hotspot row for H662.
- Gene-level literature supports SF3B1 mutation clustering
- but the available evidence did not confirm codon 662 as a qualifying hotspot.
Still missing
- No direct residue-level hotspot confirmation for codon 662 was identified in the available curated sources.
Sources
BA1 The highest observed population frequency is 0.00312% in gnomAD v4.1, which is well below the 1% BA1 threshold, so BA1 is not met. Details ▾Hide ▴
BS1 The highest observed population frequency is 0.00312% in gnomAD v4.1, which is below the 0.3% BS1 threshold, so BS1 is not met. Details ▾Hide ▴
BP4 Available computational evidence does not support a benign effect: REVEL is 0.628 and BayesDel is 0.0218, both consistent with deleterious missense prediction, while SpliceAI is 0.07 and only argues against a splice effect. Details ▾Hide ▴
Evidence considered
- REVEL score 0.628
- BayesDel score 0.0218
- SpliceAI max delta score 0.07
Sources
Not assessed · 17 · no assessment recorded
PS1 No evidence was identified that another nucleotide change produces the same amino acid substitution with an established pathogenic classification, so PS1 was not assessed. Details ▾Hide ▴
Evidence considered
- ClinVar search returned no exact variant result.
Still missing
- No same-amino-acid alternate nucleotide pathogenic comparator was identified.
Sources
PS2 No confirmed de novo occurrence with parental testing was identified for this variant, so PS2 was not assessed. Details ▾Hide ▴
Evidence considered
- No de novo data were identified in the available evidence.
Still missing
- No trio-based or parent-confirmed de novo report was identified.
Sources
PS3 Published functional literature relevant to SF3B1 was identified, but the available evidence did not provide a validated functional assay directly testing p.(His662Gln), so PS3 was not applied. Details ▾Hide ▴
Evidence considered
- OncoKB linked variant-relevant curated literature.
- Available reviewed PMIDs were gene-level functional context rather than direct p.(His662Gln) assay evidence.
Still missing
- No exact-variant functional assay result was identified in the available evidence.
Sources
PM3 No evidence was identified that this variant was observed in trans with a pathogenic variant in a recessive disorder context, so PM3 was not assessed. Details ▾Hide ▴
Evidence considered
- No ClinVar submissions or case-level trans observations were identified.
Still missing
- No phase or recessive case data were identified.
Sources
PM5 No evidence was identified that a different missense change at codon 662 has an established pathogenic classification, so PM5 was not assessed. Details ▾Hide ▴
Evidence considered
- ClinVar search did not identify codon-specific classified variants for review.
Still missing
- No codon-specific pathogenic comparator was identified.
Sources
PM6 No assumed de novo occurrence without full parental confirmation was identified for this variant, so PM6 was not assessed. Details ▾Hide ▴
Evidence considered
- No de novo evidence was identified in the available sources.
Still missing
- No de novo case report lacking complete confirmation was identified.
Sources
PP1 No segregation data were identified for this variant in affected family members, so PP1 was not assessed. Details ▾Hide ▴
Evidence considered
- No family-based evidence was identified in the available sources.
Still missing
- No family segregation data were identified.
Sources
PP2 Available evidence does not establish a gene-specific missense-constraint rule for SF3B1 that would justify PP2, so this criterion was not assessed. Details ▾Hide ▴
Evidence considered
- No CSPEC/VCEP or local gene-specific framework was available for SF3B1.
Still missing
- No gene-specific missense mechanism rule was identified.
PP4 No patient phenotype or disease-specific clinical presentation was provided that is highly specific for a single-gene disorder caused by SF3B1, so PP4 was not assessed. Details ▾Hide ▴
Evidence considered
- No phenotype packet or case-specific clinical features were identified in the reviewed files.
Still missing
- No phenotype details were available for phenotype-specific assessment.
PP5 No germline reputable-source pathogenic classification for this variant was identified, so PP5 was not assessed. Details ▾Hide ▴
Evidence considered
- This variant is absent from ClinVar.
Still missing
- No qualifying germline pathogenic classification was identified.
Sources
BS2 This variant is very rare in population databases and no evidence was identified showing occurrence in healthy adults at a frequency sufficient for BS2, so BS2 was not assessed. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 shows 7 alleles and 0 homozygotes.
Still missing
- No healthy adult observation evidence with disease-specific interpretation was identified.
Sources
BS3 No well-established functional study was identified showing normal function for p.(His662Gln), so BS3 was not applied. Details ▾Hide ▴
Evidence considered
- Reviewed literature provided SF3B1 functional context but not normal-function evidence for p.(His662Gln).
Still missing
- No benign-direction exact-variant functional evidence was identified.
Sources
BS4 No non-segregation data were identified for this variant in affected families, so BS4 was not assessed. Details ▾Hide ▴
Evidence considered
- No family-level segregation records were identified.
Still missing
- No family non-segregation evidence was identified.
Sources
BP2 No evidence was identified that this variant occurs in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant, so BP2 was not assessed. Details ▾Hide ▴
Evidence considered
- No case-level phasing information was identified.
Still missing
- No phase data were identified.
Sources
BP3 No evidence was identified that this variant lies in a repetitive region without known function, so BP3 was not assessed. Details ▾Hide ▴
Evidence considered
- No repetitive-region evidence was provided in the reviewed files.
Still missing
- No repeat-region annotation was identified.
BP5 No alternate molecular diagnosis or independent cause for disease was provided, so BP5 was not assessed. Details ▾Hide ▴
Evidence considered
- No alternate diagnosis information was identified in the reviewed files.
Still missing
- No case-specific alternate diagnosis information was available.
BP6 No reputable benign classification for this variant was identified, so BP6 was not assessed. Details ▾Hide ▴
Evidence considered
- This variant is absent from ClinVar.
Still missing
- No qualifying benign classification was identified.
Sources
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant, not a nonsense, frameshift, or canonical +/-1 or 2 splice-site variant, so the generic PVS1 null-variant framework does not apply. Details ▾Hide ▴
Evidence considered
- SF3B1 was marked eligible for generic PVS1 consideration at the gene level
- but NM_012433.2:c.1986C>A was placed outside the default null-variant buckets.
- Predicted protein consequence is p.(His662Gln) / p.(H662Q).
Sources
PM4 N/AThis variant is a missense substitution and does not cause a protein length change, so PM4 does not apply. Details ▾Hide ▴
Evidence considered
- Predicted consequence is p.(His662Gln) / p.(H662Q).
BP1 N/ABP1 does not apply because SF3B1 is not a gene in which only truncating variants are known to cause disease while missense variation is generally benign. Details ▾Hide ▴
Evidence considered
- Available SF3B1 disease and oncology literature includes clinically relevant missense variation.
Sources
pvs1_gene_context
BP7 N/ABP7 does not apply because this variant is missense rather than a synonymous or deep intronic change. Details ▾Hide ▴
Evidence considered
- Predicted consequence is p.(His662Gln) / p.(H662Q).
Identifiers
- Gene
- SF3B1
- Transcript
- NM_012433.2
- Coding (HGVS c.)
- NM_012433.2:c.1986C>A
- Protein (HGVS p.)
- NP_036565.2:p.(His662Gln)
- GRCh38
- chr2:197402647 G>T
- GRCh37
- chr2:198267371 G>T
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
7 / 1,613,874 alleles
AF 4.34e-06 · 0 homozygotes · FAF 6.8e-07
gnomAD v2.1
0 / 251,370 alleles
AF 0 · 0 homozygotes
By genetic ancestry
gnomAD v4.1
AF 4.3e-06 · 7 / 1,613,874 alleles · 0 hom · FAF 6.8e-07
| European (Finnish)2 / 64,030 | 3.1e-05 |
| African/African American1 / 74,916 | 1.3e-05 |
| South Asian1 / 91,086 | 1.1e-05 |
| European (non-Finnish)3 / 1,179,872 | 2.5e-06 |
0 alternate alleles recorded in 6 other groups: Remaining individuals, Admixed American, Amish, East Asian, Middle Eastern, Ashkenazi Jewish.
gnomAD v2.1
AF 0 · 0 / 251,370 alleles · 0 hom
No alternate alleles recorded in the displayed ancestry groups.
Statements
gnomAD v4.1
This 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 v2.1
This 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).
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 SupportingMultiple computational predictors support a deleterious missense effect: REVEL is 0.628, above a supportive threshold of 0.6, and BayesDel is 0.0218, above 0; SpliceAI shows a maximum delta score of 0.07, below 0.2, which does not support a splice effect but does not negate protein-level deleterious prediction. Details ▾Hide ▴
Evidence considered
- REVEL score 0.628
- BayesDel score 0.0218
- SpliceAI max delta score 0.07
Sources
BP4 Available computational evidence does not support a benign effect: REVEL is 0.628 and BayesDel is 0.0218, both consistent with deleterious missense prediction, while SpliceAI is 0.07 and only argues against a splice effect. Details ▾Hide ▴
Evidence considered
- REVEL score 0.628
- BayesDel score 0.0218
- SpliceAI max delta score 0.07
Sources
BP7 N/ABP7 does not apply because this variant is missense rather than a synonymous or deep intronic change. Details ▾Hide ▴
Evidence considered
- Predicted consequence is p.(His662Gln) / p.(H662Q).
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07). REVEL score = 0.628. BayesDel score = 0.0218.
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
7 / 1,613,874 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/?term=NM_012433.2%3Ac.1986C%3EA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/2-198267371-G-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr2-197402647-G-T?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_012433.2%3Ac.1986…
- OncoKB ↗www.oncokb.org/gene/SF3B1/H662Q
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=112685566
- 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= 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 v2.1
This 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).
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07). REVEL score = 0.628. BayesDel score = 0.0218.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV59205547, n = 26 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.