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SF3B1c.2352G>AUncertain significance
Print report
Variant interpretation report

SF3B1 c.2352G>A, p.(Met784Ile)

NM_012433.3:c.2352G>A NP_036565.2:p.(Met784Ile) View identifiers
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.

About SF3B1

No gene-level summary was recorded for this case.

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: 1
Pathogenic criteria applied · 1
PM2Moderate
PM2 · moderate

The variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada population databases (allele frequency = 0.0). Under generic ACMG/AMP 2015, absence from large population cohorts meets PM2 at moderate strength for a dominant disorder with AF well below 0.1%.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

Multiple lines of computational evidence suggest no significant impact on the gene product. BayesDel predicts a benign score of 0.179 (below the damaging threshold of ~0.27). SpliceAI predicts no splicing alteration (max delta score = 0.02). REVEL score of 0.538 is intermediate and does not overturn the two concordant benign/neutral predictions.

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, BP4 supporting benign; combination = 1 moderate + 1 supporting benign, 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.

SpliceAI score
0.020 maximum delta

Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. SF3B1, a component of the spliceosome complex, is frequently mutated in hematologic malignancies.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
1 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV106472208, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
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 · 10 not met · 10 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_012433.3:c.2352G>A (p.Met784Ile) is a missense variant in SF3B1, a gene encoding a core spliceosome component associated with both somatic malignancy and constitutional neurodevelopmental disorders.

The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases (allele frequency = 0.0), meeting PM2 at moderate strength.

Multiple in silico predictors suggest no significant impact: BayesDel score is 0.179 (benign range) and SpliceAI predicts no splicing alteration (max delta = 0.02), meeting BP4 at supporting benign strength. REVEL score of 0.538 is intermediate.

The variant is absent from ClinVar and has not been reported in the published literature as a germline variant. COSMIC records one somatic occurrence (COSV106472208) without functional characterization.

No variant-specific functional studies (PS3), de novo observations (PS2/PM6), co-segregation data (PP1), or case-control data (PS4) are available. Computational evidence is equivocal (PP3 not met). No pathogenic comparator at the same residue exists (PM5 not met).

The variant does not lie in a statistically significant hotspot (cancerhotspots.org) and position 784 is not a recognized recurrent mutation site (PM1 not met). SF3B1 germline disease involves both missense and loss-of-function variants (PMID:41577671), so BP1 does not apply.

With one moderate pathogenic criterion (PM2) and one supporting benign criterion (BP4), the evidence is insufficient for classification. The variant remains a Variant of Uncertain Significance (VUS) under ACMG/AMP 2015 generic rules.

Met · 2

PM2 ModerateThe variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada population databases (allele frequency = 0.0). Under generic ACMG/AMP 2015, absence from large population cohorts meets PM2 at moderate strength for a dominant disorder with AF well below 0.1%. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (0 alleles). Absent from gnomAD v4.1 (0 alleles). Absent from gnomAD-Canada v1.0 (0 alleles). Allele frequency 0.0
  • well below the 0.1% PM2 threshold.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP4 SupportingMultiple lines of computational evidence suggest no significant impact on the gene product. BayesDel predicts a benign score of 0.179 (below the damaging threshold of ~0.27). SpliceAI predicts no splicing alteration (max delta score = 0.02). REVEL score of 0.538 is intermediate and does not overturn the two concordant benign/neutral predictions. Details ▾Hide ▴
Evidence considered
  • BayesDel: 0.179 (benign). SpliceAI max delta: 0.02 (no splicing impact). REVEL: 0.538 (intermediate). Two of three in silico predictors support no damaging effect.
Sources
revelbayesdelspliceai ↗

Not met · 10 · evaluated, threshold not reached

PS1 No alternative nucleotide change at codon 784 producing the same amino acid change (p.Met784Ile) has been established as pathogenic. PS1 requires a different nucleotide substitution resulting in the identical amino acid change with an established pathogenic classification. Details ▾Hide ▴
Evidence considered
  • No ClinVar entries for any variant at codon 784
  • no literature reports of an alternative nucleotide change producing p.Met784Ile with a pathogenic classification.
Still missing
  • No data on alternate nucleotide substitutions at codon 784.
PS3 No variant-specific functional studies have been performed for NM_012433.3:c.2352G>A (p.Met784Ile). OncoKB reports Unknown Oncogenic Effect with no curated functional evidence. The single COSMIC somatic report (COSV106472208) lacks functional characterization and does not meet PS3 requirements. Details ▾Hide ▴
Evidence considered
  • OncoKB: Unknown Oncogenic Effect
  • no variant-specific functional data. COSMIC: one somatic occurrence without functional characterization. No PMIDs with functional data for this variant.
Still missing
  • Functional studies (e.g.
  • splicing assays
  • complementation assays) for this specific variant are absent.
Sources
oncokb ↗
PM1 The variant (p.Met784Ile) does not lie within a statistically significant mutational hotspot per cancerhotspots.org, and position 784 is not a recognized recurrent somatic mutation site in SF3B1. While SF3B1 HEAT domain mutations are common in cancer, the known hotspots cluster at residues K700, R625, K666, H662, and E902 — not at M784. Without residue-specific hotspot or critical functional domain evidence for position 784, PM1 is not met. Details ▾Hide ▴
Evidence considered
  • cancerhotspots.org: residue not significant. OncoKB: no curated hotspot at M784. Known SF3B1 somatic hotspots (K700E
  • R625
  • K666
  • H662
  • E902) are distinct from position 784.
Still missing
  • No literature characterizing position 784 as a critical functional residue.
Sources
oncokb ↗
PM5 No pathogenic missense variant at the same amino acid residue (Met784) has been identified. PM5 requires a different missense change at the same codon with an established pathogenic classification. The automated PM5 candidate search returned zero same-residue candidates. Details ▾Hide ▴
Evidence considered
  • PM5 candidate search: 0 same-residue candidates identified. No ClinVar entries for any missense variant at codon 784.
Still missing
  • No known pathogenic comparator at residue 784.
Sources
pm5_candidates
PP3 Multiple lines of computational evidence do not support a deleterious effect. REVEL score is 0.538 (intermediate, below the typical pathogenic threshold of >0.75). BayesDel score is 0.179 (below the damaging threshold of ~0.27). SpliceAI predicts no splicing impact (max delta = 0.02). The in silico evidence is equivocal and does not meet PP3 requirements for multiple concordant damaging predictions. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.538 (intermediate). BayesDel: 0.179 (benign range). SpliceAI max delta: 0.02 (no splicing effect). Two of three predictors indicate no significant impact.
Sources
revelbayesdelspliceai ↗
BA1 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (allele frequency = 0.0). BA1 requires an allele frequency >1% in population databases. Details ▾Hide ▴
Evidence considered
  • Allele frequency 0.0 across all gnomAD cohorts
  • well below 1% BA1 threshold.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (allele frequency = 0.0). BS1 requires an allele frequency >0.3% under non-VCEP generic ACMG rules. Details ▾Hide ▴
Evidence considered
  • Allele frequency 0.0 across all gnomAD cohorts
  • well below 0.3% BS1 threshold.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS2 The variant has not been observed in any healthy individuals in population databases. BS2 requires observation in a healthy adult homozygous state (for a dominant disorder) or in trans with a pathogenic variant (for a recessive disorder). Details ▾Hide ▴
Evidence considered
  • Variant absent from all population databases
  • no healthy homozygous carriers observed.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BP1 SF3B1 germline disease is associated with both missense and loss-of-function variants. A recent cohort study (PMID:41577671) reports 17 individuals with constitutional missense variants and 9 with predicted loss-of-function variants, both associated with neurodevelopmental disorders. Missense variants are a well-established disease mechanism in SF3B1, so BP1 does not apply. Details ▾Hide ▴
Evidence considered
  • PMID:41577671: 17 missense and 9 LoF variants in SF3B1 neurodevelopmental disorder cohort. Missense variants are a recognized disease mechanism.
BP6 The variant is absent from ClinVar; no reputable source has classified this variant as benign or likely benign. Details ▾Hide ▴
Evidence considered
  • ClinVar: variant not present
  • no benign classification from any submitter.
Sources
clinvar ↗

Not assessed · 10 · no assessment recorded

PS2 No de novo testing data with confirmed paternity and maternity is available for this variant. Details ▾Hide ▴
Still missing
  • De novo testing data not available.
PS4 No case-control or cohort prevalence data are available to assess enrichment of this variant in affected individuals compared to controls. Details ▾Hide ▴
Still missing
  • No affected-vs-control prevalence data available.
PM6 No de novo observation data are available for this variant. PM6 requires reported de novo occurrence without confirmed paternity and maternity. Details ▾Hide ▴
Still missing
  • No de novo testing data available.
PP1 No family co-segregation data are available for this variant. Details ▾Hide ▴
Still missing
  • No segregation data available.
PP2 HCI prior constraint data are not available for SF3B1; the gene is not in the HCI prior database. Without a gene-level missense constraint metric (z-score or HCI prior), the low rate of benign missense variation cannot be determined for PP2. Details ▾Hide ▴
Evidence considered
  • HCI prior: gene not supported
  • no probability score.
Still missing
  • No gene-level missense constraint metric (HCI prior
  • missense z-score) available for SF3B1.
PP4 No patient phenotype or clinical data are available to assess whether the presentation is highly specific for SF3B1-related disease. Details ▾Hide ▴
Still missing
  • No patient phenotype data provided.
BS3 No well-established functional studies demonstrating no deleterious effect are available for this variant. Details ▾Hide ▴
Still missing
  • No functional studies available for this variant.
BS4 No family segregation data demonstrating non-segregation with disease are available. Details ▾Hide ▴
Still missing
  • No segregation data available.
BP2 No data on observation of this variant in trans with a known pathogenic dominant variant are available. Details ▾Hide ▴
Still missing
  • No trans-phase data available.
BP5 No data are available to determine whether an alternative molecular basis for disease has been identified in a case carrying this variant. Details ▾Hide ▴
Still missing
  • No alternative molecular diagnosis data available.
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (p.Met784Ile); PVS1 applies only to null variants (nonsense, frameshift, canonical ±1,2 splice consensus). The generic PVS1 framework assessment confirms variant_bucket='other' and does not trigger PVS1. Details ▾Hide ▴
Evidence considered
  • Missense variant in exon 16
  • not a null variant. PVS1 decision tree yields not_applicable per ClinGen SVI PVS1 recommendations (PMC6185798).
Sources
pvs1_generic_framework ↗
PM3 N/APM3 applies to recessive disorders where the variant is observed in trans with a pathogenic variant; SF3B1-associated disorders follow autosomal dominant inheritance. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 applies to protein length-altering variants (in-frame indels, stop-loss); this is a missense substitution. Details ▾Hide ▴

No further detail was recorded.

PP5 N/APP5 is not a standard ACMG/AMP 2015 criterion. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ABP3 applies to in-frame indels in repetitive regions; this is a substitution variant. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ANM_012433.3:c.2352G>A is a missense variant (p.Met784Ile), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splicing impact. Details ▾Hide ▴
Evidence considered
  • Missense substitution (G>A) at position 2352 producing p.Met784Ile.
PS5 N/APS5 is not a standard ACMG/AMP 2015 criterion. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
SF3B1
Transcript
NM_012433.3
Coding (HGVS c.)
NM_012433.3:c.2352G>A
Protein (HGVS p.)
NP_036565.2:p.(Met784Ile)
GRCh38
chr2:197401760 C>T
GRCh37
chr2:198266484 C>T
COSMIC
COSV106472208

Gene diagram

Every interpreted variant in SF3B1, mapped onto the exon structure of NM_012433.3. Select a row to find it on the plot.

SF3B1NM_012433.3
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +73 bp
0.020
SpliceAI acceptor gainat +149 bp
0.000
SpliceAI donor lossat -18 bp
0.000
SpliceAI donor gainat +290 bp
0.000
Pangolin splice lossmagnitude shown
-0.010
Pangolin splice gain
0.000

Other predictors

REVEL
0.538
BayesDel
0.179

How the predictions were used

BP4 SupportingMultiple lines of computational evidence suggest no significant impact on the gene product. BayesDel predicts a benign score of 0.179 (below the damaging threshold of ~0.27). SpliceAI predicts no splicing alteration (max delta score = 0.02). REVEL score of 0.538 is intermediate and does not overturn the two concordant benign/neutral predictions. Details ▾Hide ▴
Evidence considered
  • BayesDel: 0.179 (benign). SpliceAI max delta: 0.02 (no splicing impact). REVEL: 0.538 (intermediate). Two of three in silico predictors support no damaging effect.
Sources
revelbayesdelspliceai ↗
PP3 Multiple lines of computational evidence do not support a deleterious effect. REVEL score is 0.538 (intermediate, below the typical pathogenic threshold of >0.75). BayesDel score is 0.179 (below the damaging threshold of ~0.27). SpliceAI predicts no splicing impact (max delta = 0.02). The in silico evidence is equivocal and does not meet PP3 requirements for multiple concordant damaging predictions. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.538 (intermediate). BayesDel: 0.179 (benign range). SpliceAI max delta: 0.02 (no splicing effect). Two of three predictors indicate no significant impact.
Sources
revelbayesdelspliceai ↗
BP7 N/ANM_012433.3:c.2352G>A is a missense variant (p.Met784Ile), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splicing impact. Details ▾Hide ▴
Evidence considered
  • Missense substitution (G>A) at position 2352 producing p.Met784Ile.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.538. BayesDel score = 0.179088.

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 Captured gnomAD v4.1 source record 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

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

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). REVEL score = 0.538. BayesDel score = 0.179088.

Functional

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. SF3B1, a component of the spliceosome complex, is frequently mutated in hematologic malignancies.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV106472208, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.