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SF3B1
Final classification
Likely Pathogenic
SF3B1 c.2359del · p.Ile787LeufsTer3
SF3B1

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).

Gene
SF3B1
Transcript
NM_012433.2
HGVS · transcript:coding
NM_012433.2:c.2359del
Consequence
N/A
GRCh38
chr2:197401752 AT>A
GRCh37
chr2:198266476 AT>A
Basis 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. ▾
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.
Classification rationale
PVS1PM2 Likely Pathogenic
SF3B1 c.2359del

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).1 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.2 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).3

PVS1 + PM2 → Likely Pathogenic
1 pvs1_generic_framework ↗pvs1_variant_assessment
2 gnomad_v2 ↗gnomad_v4 ↗
3 generic_acmg_combination_rules
Gene diagram · NM_012433.2 · variants mapped to exon structure
SF3B1 NM_012433.2
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 5 assessed
Applied · 2
Strength Supporting Moderate Strong Very strong
✓
PVS1 very strong Pathogenic
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.
Frameshift variant predicted to produce truncated protein p.I787Lfs*3 with NMD-competent premature termination codonSF3B1 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
pvs1_generic_framework ↗
✓
PM2 moderate Pathogenic
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.
Absent from gnomAD v2.1 (exomes)Absent from gnomAD v4.1 (0/1609
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
Assessed · not applied
Pathogenic
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.
PP3 Multiple lines of computational evidence do not independently support a deleterious effect beyond what is already captured by PVS1.
Benign
BA1 The allele frequency in population databases is 0.00%, which does not exceed the 1% threshold for BA1.
BS1 The allele frequency in population databases is 0.00%, which does not exceed the 0.3% threshold for BS1.
BP4 Multiple lines of computational evidence do not suggest no impact.
N/A · 21 PS1 · PS2 · PS3 · PS4 · PM3 · PM4 · PM5 · PM6 · PP1 · PP2 · PP4 · PP5 · BS2 · BS3 · BS4 · BP1 · BP2 · BP3 · BP5 · BP6 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
gnomAD v2.1
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).
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent · 0 / 1,609,404
0 hom
Not observed in any ancestry group.
+ 10 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))
gnomAD v2.1
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗
ClinVar screenshot
ClinVar
This variant is absent from ClinVar.
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
SpliceAI ↗
Functional / OncoKB screenshot
Functional Unknown Oncogenic Effect
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
OncoKB ↗
COSMIC screenshot
COSMIC
Cancer hotspots screenshot
Cancer hotspots
Somatic evidence Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV59220730, n = 3 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
COSMIC ↗ Hotspots ↗
Sources & reference links
8Sources
ClinVar
gnomAD v2.1
gnomAD v4.1
gnomAD-Canada
SpliceAI
OncoKB
COSMIC
Cancer hotspots