About SF3B1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
SF3B1 c.2359del, p.(Ile787LeufsTer3)
Classification
Likely pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely pathogenic classification under the recorded framework.
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: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Very strong
PVS1 · very strong
NM_012433.2:c.2359del is a frameshift deletion predicted to cause premature termination at codon 789 (p.Ile787LeufsTer3), with the premature termination codon located well upstream of the normal terminus (residue 1305) in a gene where loss of function is an established disease mechanism for germline neurodevelopmental disorders.
PM2Moderate
PM2 · moderate
This variant is absent from large population databases including gnomAD v2.1 and v4.1 (0/1,609,404 alleles), supporting rarity in the general population.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Likely pathogenic
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 very strong, PM2 moderate; combination = 1 very strong + 1 moderate, which maps to Likely Pathogenic.
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
0 / 1,609,404 alleles
gnomAD v4.1: 0 / 1,609,404 alleles. Recorded AF 0. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.020 maximum delta
Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
3 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV59220730, n = 3 times).
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.
29 criteria with recorded statuses: 2 met · 5 not met · 0 not assessed · 22 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
PVS1 (very_strong): NM_012433.2:c.2359del is a frameshift deletion predicted to cause premature termination (p.Ile787LeufsTer3) in SF3B1, a gene in which germline loss of function is an established disease mechanism for neurodevelopmental disorders (PMC6185798; PMID:41577671).
PM2 (moderate): This variant is absent from large population databases including gnomAD v2.1 and v4.1 (0/1,609,404 alleles), consistent with rarity in the general population.
Classification of Likely Pathogenic is assigned based on 1 very strong criterion (PVS1) and 1 moderate criterion (PM2) under the generic ACMG/AMP 2015 combination rules (PMID:25741868).
No criteria match.
Met · 2
PVS1 Very strongNM_012433.2:c.2359del is a frameshift deletion predicted to cause premature termination at codon 789 (p.Ile787LeufsTer3), with the premature termination codon located well upstream of the normal terminus (residue 1305) in a gene where loss of function is an established disease mechanism for germline neurodevelopmental disorders. Details ▾Hide ▴
Evidence considered
- Frameshift variant predicted to produce truncated protein p.I787Lfs*3 with NMD-competent premature termination codon
- SF3B1 germline loss-of-function mechanism supported by literature (PMID:41577671 reports 9 individuals with predicted LoF variants in neurodevelopmental disorder cohort)
- Variant located at c.2359
- approximately 60% through the CDS
- consistent with NMD triggering
Still missing
- Exon boundaries not resolved by Mutalyzer
- unable to confirm exact exon and precise NMD-rule compliance computationally
- NM_012433.2 is not the current RefSeq select transcript
- NM_012433.4 was flagged as more recent
Sources
PM2 ModerateThis variant is absent from large population databases including gnomAD v2.1 and v4.1 (0/1,609,404 alleles), supporting rarity in the general population. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (exomes)
- Absent from gnomAD v4.1 (0/1
- 609
- 404 alleles
- 0 homozygotes)
- Absent from gnomAD-Canada v1.0
Sources
Not met · 5 · evaluated, threshold not reached
PM1 This variant does not lie in a statistically significant mutational hotspot and is not located in a critical functional domain identified as a hotspot for pathogenic variation. Details ▾Hide ▴
Evidence considered
- Variant not listed in any mutational hotspot resource
- Hotspot analysis confirms residue is not in a statistically significant cluster
PP3 Multiple lines of computational evidence do not independently support a deleterious effect beyond what is already captured by PVS1. REVEL and BayesDel are unavailable for this deletion variant, and SpliceAI predicts no significant splice impact (max delta score 0.02). Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.02 — no significant splice alteration predicted
- REVEL and BayesDel not available for non-SNV variant type
Sources
BA1 The allele frequency in population databases is 0.00%, which does not exceed the 1% threshold for BA1. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 allele frequency 0.00% (0/1
- 609
- 404 alleles)
Sources
BS1 The allele frequency in population databases is 0.00%, which does not exceed the 0.3% threshold for BS1. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 allele frequency 0.00% (0/1
- 609
- 404 alleles)
Sources
BP4 Multiple lines of computational evidence do not suggest no impact. SpliceAI predicts no significant splice alteration (max delta 0.02), but the frameshift itself is inherently damaging and no computational evidence supports a benign effect on the truncated protein product. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.02 — no significant splice alteration predicted
- but does not address protein-level impact of frameshift
Sources
Not applicable · 22· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 applies to nucleotide substitutions producing the same amino acid change as an established pathogenic variant; this variant is a frameshift deletion. Details ▾Hide ▴
No further detail was recorded.
PS2 N/ANo de novo observations are available for this variant in ClinVar, literature, or any evidence source. Details ▾Hide ▴
No further detail was recorded.
PS3 N/ANo well-established in vitro or in vivo functional studies were identified for this specific variant. Details ▾Hide ▴
No further detail was recorded.
PS4 N/ANo case-control or statistical prevalence data are available for this variant. Details ▾Hide ▴
No further detail was recorded.
PM3 N/ASkipped per instruction — trivially not applicable. Details ▾Hide ▴
No further detail was recorded.
PM4 N/APM4 applies to in-frame deletions/insertions or stop-loss variants; this is a frameshift deletion, which is assessed under PVS1. Details ▾Hide ▴
No further detail was recorded.
PM5 N/APM5 applies to novel missense variants at residues with established pathogenic missense changes; this is a frameshift variant. Details ▾Hide ▴
No further detail was recorded.
PM6 N/ANo de novo observation data available for this variant. Details ▾Hide ▴
No further detail was recorded.
PP1 N/ANo cosegregation data with disease in multiple affected family members is available. Details ▾Hide ▴
No further detail was recorded.
PP2 N/APP2 applies to missense variants in genes with low rate of benign missense variation; this is a frameshift variant. Details ▾Hide ▴
No further detail was recorded.
PP4 N/ANo patient phenotype or family history data are available to assess specificity for a disease with a single genetic etiology. Details ▾Hide ▴
No further detail was recorded.
PP5 N/ANo reputable source has reported this variant as pathogenic; the variant is absent from ClinVar. Details ▾Hide ▴
No further detail was recorded.
BS2 N/AThe variant is absent from population databases; no observation in healthy adult individuals is available to contradict pathogenicity. Details ▾Hide ▴
No further detail was recorded.
BS3 N/ANo well-established in vitro or in vivo functional studies demonstrating no damaging effect are available for this variant. Details ▾Hide ▴
No further detail was recorded.
BS4 N/ANo family segregation data are available to assess lack of segregation with disease. Details ▾Hide ▴
No further detail was recorded.
BP1 N/ABP1 applies to missense variants in genes where primarily truncating variants cause disease; this variant itself is truncating. Details ▾Hide ▴
No further detail was recorded.
BP2 N/ANo data available regarding observation in trans with a pathogenic variant or in cis with a pathogenic variant. Details ▾Hide ▴
No further detail was recorded.
BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions; this is a frameshift variant. Details ▾Hide ▴
No further detail was recorded.
BP5 N/ANo data available regarding an alternate molecular basis for disease in a case harboring this variant. Details ▾Hide ▴
No further detail was recorded.
BP6 N/ANo reputable source has reported this variant as benign; the variant is absent from ClinVar. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact; this is a frameshift deletion. Details ▾Hide ▴
No further detail was recorded.
PS5 N/ANo reputable source has reported this variant as pathogenic with evidence unavailable for independent evaluation; the variant is absent from ClinVar. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- SF3B1
- Transcript
- NM_012433.2
- Coding (HGVS c.)
- NM_012433.2:c.2359del
- Protein (HGVS p.)
- NP_036565.2:p.(Ile787LeufsTer3)
- GRCh38
- chr2:197401752 AT>A
- GRCh37
- chr2:198266476 AT>A
- COSMIC
- COSV59220730
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
0 / 1,609,404 alleles
AF 0 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 0 · 0 / 1,609,404 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= 0; MAF= 0.00000%, 0/1609404 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/74764 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 Multiple lines of computational evidence do not independently support a deleterious effect beyond what is already captured by PVS1. REVEL and BayesDel are unavailable for this deletion variant, and SpliceAI predicts no significant splice impact (max delta score 0.02). Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.02 — no significant splice alteration predicted
- REVEL and BayesDel not available for non-SNV variant type
Sources
BP4 Multiple lines of computational evidence do not suggest no impact. SpliceAI predicts no significant splice alteration (max delta 0.02), but the frameshift itself is inherently damaging and no computational evidence supports a benign effect on the truncated protein product. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.02 — no significant splice alteration predicted
- but does not address protein-level impact of frameshift
Sources
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact; this is a frameshift deletion. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
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
0 / 1,609,404 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.020
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.2359del
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/2-198266476-AT-A?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr2-197401752-AT-A?dataset=g…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/2-197401752-AT-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_012433.2%3Ac.2359…
- OncoKB ↗www.oncokb.org/gene/SF3B1/I787Lfs*3
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=126505776
- 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= 0; MAF= 0.00000%, 0/1609404 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/74764 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
Functional
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV59220730, n = 3 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.