About SF3B1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
SF3B1 c.1866G>T, p.(Glu622Asp)
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: 1
Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Moderate
PM2 · moderate
This variant is absent from gnomAD v2.1 and is present at very low frequency in gnomAD v4.1 with AF 2.478382310298422e-06 (0.00025%, 4/1613956 alleles), which is below the default PM2 threshold of 0.1%. This rarity supports PM2.
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; combination = 1 moderate, 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
4 / 1,613,956 alleles
gnomAD v4.1: 4 / 1,613,956 alleles. Recorded AF 2.47838e-06. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
No listed criterion applied
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: 1 met · 5 not met · 16 not assessed · 6 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.1866G>T (p.Glu622Asp; p.E622D) variant has been observed in somatic cancer resources and has not been reported in ClinVar.
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%.
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.
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.
No criteria match.
Met · 1
PM2 ModerateThis variant is absent from gnomAD v2.1 and is present at very low frequency in gnomAD v4.1 with AF 2.478382310298422e-06 (0.00025%, 4/1613956 alleles), which is below the default PM2 threshold of 0.1%. This rarity supports PM2. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1.
- Present in gnomAD v4.1 at AF 2.478382310298422e-06.
Sources
Not met · 5 · evaluated, threshold not reached
PM1 Published studies show that recurrent SF3B1 missense variants cluster in the HEAT-repeat region, but the available hotspot review did not identify p.Glu622Asp or codon 622 as a statistically significant hotspot. Nearby regional clustering alone is not sufficient to apply PM1 for this variant. Details ▾Hide ▴
Evidence considered
- Cancer Hotspots review reported no significant hotspot at this residue.
- Gene-level literature supports regional clustering of SF3B1 missense variants.
Still missing
- No direct codon-level recurrence evidence for residue 622 was identified.
Sources
PP3 Available computational evidence is mixed rather than consistently damaging. REVEL is 0.455, BayesDel is -0.0897007, and SpliceAI shows a possible splice effect with max delta score 0.27, so the in silico evidence does not provide a clear basis to apply PP3. Details ▾Hide ▴
Evidence considered
- REVEL 0.455.
- BayesDel -0.0897007.
- SpliceAI max delta score 0.27.
Still missing
- No gene-specific computational threshold framework was identified.
Sources
BA1 The observed gnomAD v4.1 allele frequency is 2.478382310298422e-06 (0.00025%), which is well below the default BA1 threshold of 1%, so BA1 is not met. Details ▾Hide ▴
BS1 The observed gnomAD v4.1 allele frequency is 2.478382310298422e-06 (0.00025%), which is below the default BS1 threshold of 0.3%, so BS1 is not met. Details ▾Hide ▴
BP4 Available computational evidence does not provide a clearly benign prediction. REVEL is 0.455, BayesDel is -0.0897007, and SpliceAI predicts a possible splice effect with max delta score 0.27, so BP4 is not supported. Details ▾Hide ▴
Evidence considered
- REVEL 0.455.
- BayesDel -0.0897007.
- SpliceAI max delta score 0.27.
Still missing
- No gene-specific computational threshold framework was identified.
Sources
Not assessed · 16 · no assessment recorded
PS1 No evidence was identified showing that this exact amino acid change, p.Glu622Asp (p.E622D), matches a previously established pathogenic variant caused by a different nucleotide change. Details ▾Hide ▴
Still missing
- No qualifying prior pathogenic amino acid match was identified.
PS2 No confirmed de novo occurrence with parental confirmation was identified for this variant. Details ▾Hide ▴
Still missing
- No parentage-confirmed de novo case report was identified.
PS3 Published studies show that SF3B1 alterations can disrupt splicing and cell function, but no well-established functional study specific to p.Glu622Asp was identified. Available gene-level functional literature therefore does not support applying PS3 to this exact variant. Details ▾Hide ▴
Evidence considered
- Gene-level functional literature on SF3B1 was reviewed.
- No exact-variant functional result for p.Glu622Asp was identified.
Still missing
- No exact-variant functional assay was identified.
- No validated study directly demonstrating a damaging effect of p.Glu622Asp was identified.
Sources
PS4 This variant has variant-specific somatic cancer context, but no germline case-control or affected-individual enrichment data were identified to show that it is significantly more common in affected individuals than in controls. Details ▾Hide ▴
PM3 No evidence was identified showing this variant in trans with a pathogenic variant in a recessive disorder. Details ▾Hide ▴
Still missing
- No allelic phase or recessive case data were identified.
PM5 No evidence was identified showing a different pathogenic missense change at codon 622 that would support PM5 for this novel amino acid substitution. Details ▾Hide ▴
Still missing
- No qualifying pathogenic missense variant at the same codon was identified.
PM6 No assumed de novo occurrence without full parental confirmation was identified for this variant. Details ▾Hide ▴
Still missing
- No de novo case report without confirmed parentage was identified.
PP1 No segregation data were identified for this variant. Details ▾Hide ▴
Still missing
- No family study or pedigree data were identified.
PP2 SF3B1 is known to harbor disease-relevant missense variation, but no gene-specific missense constraint rule or calibrated framework was identified here to support PP2 for this variant. Details ▾Hide ▴
Still missing
- No qualifying gene-specific PP2 framework was identified.
PP4 No phenotype information was provided that is sufficiently specific for a single-gene or narrow differential diagnosis assessment. Details ▾Hide ▴
Still missing
- No case phenotype was available for PP4 review.
BS2 This variant is rare in population databases and no evidence was identified showing observation in healthy adults in a manner sufficient to apply BS2. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 reported 4 alleles and 0 homozygotes.
Still missing
- No qualifying adult observation dataset or phenotype-negative carrier evidence was identified.
Sources
BS3 No well-established functional study showing no damaging effect for p.Glu622Asp was identified. Details ▾Hide ▴
Evidence considered
- Gene-level functional literature was reviewed.
- No exact-variant neutral functional result was identified.
Still missing
- No exact-variant benign functional assay was identified.
Sources
BS4 No non-segregation evidence was identified for this variant. Details ▾Hide ▴
Still missing
- No family data were identified to assess lack of segregation.
BP2 No phase data were identified to show this variant occurs in cis with a pathogenic variant or in trans in a manner supporting BP2. Details ▾Hide ▴
Still missing
- No allelic phase data were identified.
BP3 No evidence was identified showing that this missense change is located in a repetitive region without known function that would support BP3. Details ▾Hide ▴
Still missing
- No repeat-region evidence was identified.
BP5 No evidence was identified for an alternate molecular explanation for disease that would support BP5. Details ▾Hide ▴
Still missing
- No alternate-cause case data were identified.
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant, and available PVS1 review indicates it does not fall within the generic null-variant categories for PVS1 application such as nonsense, frameshift, or canonical +/-1 or 2 splice variants. Although SF3B1 was flagged as eligible for generic PVS1 consideration at the gene level, this specific variant type does not support PVS1. Details ▾Hide ▴
Evidence considered
- Gene-level PVS1 gate was eligible.
- Variant-level PVS1 scaffold states this missense change is outside the default generic PVS1 buckets.
Sources
PM4 N/AThis is a missense substitution and does not cause a protein length change from an in-frame insertion, in-frame deletion, or stop-loss event. Details ▾Hide ▴
Evidence considered
- Protein consequence is p.Glu622Asp.
PP5 N/AAssertion-based pathogenic evidence was not used for this review, and no qualifying external classification source was identified for this variant. Details ▾Hide ▴
BP1 N/AThis is a missense variant in a gene where disease-relevant missense variation is established, so BP1 does not apply. Details ▾Hide ▴
Evidence considered
- Published literature supports disease-relevant missense variation in SF3B1.
Sources
BP6 N/AAssertion-based benign evidence was not used for this review, and no qualifying external benign classification source was identified for this variant. Details ▾Hide ▴
BP7 N/AThis criterion is for synonymous or certain noncoding variants with no predicted splice impact, and it does not apply to this missense variant. Details ▾Hide ▴
Evidence considered
- Protein consequence is p.Glu622Asp.
Identifiers
- Gene
- SF3B1
- Transcript
- NM_012433.2
- Coding (HGVS c.)
- NM_012433.2:c.1866G>T
- Protein (HGVS p.)
- NP_036565.2:p.(Glu622Asp)
- GRCh38
- chr2:197402767 C>A
- GRCh37
- chr2:198267491 C>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
4 / 1,613,956 alleles
AF 2.48e-06 · 0 homozygotes · FAF 7.9e-07
gnomAD v2.1
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 2.5e-06 · 4 / 1,613,956 alleles · 0 hom · FAF 7.9e-07
| European (non-Finnish)4 / 1,179,986 | 3.4e-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.
Statements
gnomAD v4.1
This 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 v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 Available computational evidence is mixed rather than consistently damaging. REVEL is 0.455, BayesDel is -0.0897007, and SpliceAI shows a possible splice effect with max delta score 0.27, so the in silico evidence does not provide a clear basis to apply PP3. Details ▾Hide ▴
Evidence considered
- REVEL 0.455.
- BayesDel -0.0897007.
- SpliceAI max delta score 0.27.
Still missing
- No gene-specific computational threshold framework was identified.
Sources
BP4 Available computational evidence does not provide a clearly benign prediction. REVEL is 0.455, BayesDel is -0.0897007, and SpliceAI predicts a possible splice effect with max delta score 0.27, so BP4 is not supported. Details ▾Hide ▴
Evidence considered
- REVEL 0.455.
- BayesDel -0.0897007.
- SpliceAI max delta score 0.27.
Still missing
- No gene-specific computational threshold framework was identified.
Sources
BP7 N/AThis criterion is for synonymous or certain noncoding variants with no predicted splice impact, and it does not apply to this missense variant. Details ▾Hide ▴
Evidence considered
- Protein consequence is p.Glu622Asp.
Statement
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.27). REVEL score = 0.455. BayesDel score = -0.0897007.
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
4 / 1,613,956 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.1866G%3ET
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/2-198267491-C-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr2-197402767-C-A?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_012433.2%3Ac.1866…
- OncoKB ↗www.oncokb.org/gene/SF3B1/E622D
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=112683492
- 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= 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 v2.1
Absent from gnomAD v2.1.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.27). REVEL score = 0.455. BayesDel score = -0.0897007.
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; COSV59206479, n = 43 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.