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SF3B1c.2263C>TUncertain significance
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Variant interpretation report

SF3B1 c.2263C>T, p.(Pro755Ser)

NM_012433.3:c.2263C>T NP_036565.2:p.(Pro755Ser) 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: 2 Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM2Supporting
PM2 · supporting

This variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes), with an allele frequency well below the 0.1% PM2 threshold.

PP3Supporting
PP3 · supporting

Multiple lines of in silico evidence support a deleterious effect. REVEL score of 0.562 exceeds the 0.5 threshold for deleterious prediction. SpliceAI predicts a possible splice impact with a max delta score of 0.44 (acceptor gain, DS_AG=0.44).

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 supporting, PP3 supporting; combination = 2 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.

SpliceAI score
0.440 maximum delta

Recorded SpliceAI maximum delta score: 0.440. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · PP3 → 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; COSV59230199, 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.

26 criteria with recorded statuses: 2 met · 21 not met · 1 not assessed · 2 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_012433.3:c.2263C>T (p.Pro755Ser) in SF3B1 is a missense variant absent from population databases (gnomAD v2.1, v4.1, gnomAD-Canada), meeting PM2 at supporting strength.

In silico predictors support a deleterious effect: REVEL score 0.562 and SpliceAI max delta 0.44 (acceptor gain) meet PP3 at supporting strength.

No pathogenic or benign classifications are available in ClinVar. No variant-specific functional studies, segregation data, de novo observations, or case-control data were identified.

With two supporting pathogenic criteria (PM2 and PP3) and no benign criteria met, this variant is classified as a Variant of Uncertain Significance (VUS) per ACMG/AMP 2015 guidelines.

Met · 2

PM2 SupportingThis variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes), with an allele frequency well below the 0.1% PM2 threshold. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 exomes.
  • Absent from gnomAD v4.1 exomes.
  • Absent from gnomAD-Canada v1.0 genomes.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
PP3 SupportingMultiple lines of in silico evidence support a deleterious effect. REVEL score of 0.562 exceeds the 0.5 threshold for deleterious prediction. SpliceAI predicts a possible splice impact with a max delta score of 0.44 (acceptor gain, DS_AG=0.44). Details ▾Hide ▴
Evidence considered
  • REVEL score 0.562 (deleterious prediction).
  • SpliceAI max delta 0.44 (acceptor gain DS_AG=0.44).
  • BayesDel score 0.112595 (below deleterious threshold
  • not contributory).
Sources
revelspliceai ↗bayesdel

Not met · 21 · evaluated, threshold not reached

PS1 No prior report of this exact nucleotide change as pathogenic in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar
  • no literature reports identified.
Sources
clinvar ↗
PS2 No de novo observation with confirmed maternity and paternity is available for this variant. Details ▾Hide ▴
Evidence considered
  • No de novo data identified in any source.
Still missing
  • No parental testing data available.
PS3 No variant-specific well-established functional studies were identified. OncoKB classifies this variant as Unknown Oncogenic Effect. Details ▾Hide ▴
Evidence considered
  • OncoKB: Unknown Oncogenic Effect
  • no variant-specific functional assays found.
Still missing
  • No functional studies available for this variant.
Sources
oncokb ↗
PS4 No case-control studies comparing variant prevalence in affected individuals versus controls are available. Details ▾Hide ▴
Evidence considered
  • No case-control data identified.
Still missing
  • No affected vs. control prevalence data available.
PM1 This variant does not lie within a statistically significant mutational hotspot per Cancer Hotspots analysis, and no gene-specific functional domain PM1 rule is available. Details ▾Hide ▴
Evidence considered
  • Cancer Hotspots: residue not significant
  • exact variant not listed as recurrent hotspot.
Still missing
  • No CSPEC/VCEP-defined functional domain criteria for SF3B1.
PM5 No pathogenic missense variant has been identified at residue Pro755 to serve as a same-residue comparator. Automated PM5 candidate harvesting returned no candidates. Details ▾Hide ▴
Evidence considered
  • No same-residue pathogenic missense comparators at Pro755 found in ClinVar.
Still missing
  • No ClinVar entries for any missense at Pro755.
Sources
pm5_candidates
PM6 No de novo observation (with or without confirmed parentage) is available for this variant. Details ▾Hide ▴
Evidence considered
  • No de novo reports identified in any source.
Still missing
  • No parental data available.
PP1 No co-segregation data are available for this variant. Details ▾Hide ▴
Evidence considered
  • No family or co-segregation data identified.
Still missing
  • No family studies available.
PP4 No patient phenotype information is available for assessment of phenotypic specificity. Details ▾Hide ▴
Evidence considered
  • No phenotype data provided.
Still missing
  • Patient phenotype not available.
PP5 This variant has not been reported as pathogenic by a reputable source. It is absent from ClinVar. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar.
Sources
clinvar ↗
BA1 The variant is absent from gnomAD; the allele frequency does not exceed the 1% BA1 threshold. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 and v4.1
  • allele frequency not available (absent).
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 The variant is absent from gnomAD; the allele frequency does not exceed the 0.3% BS1 threshold. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 and v4.1.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS2 No observations of this variant in healthy adults are available to assess BS2. Details ▾Hide ▴
Evidence considered
  • No healthy adult observation data available.
Still missing
  • No healthy control data.
BS3 No well-established functional studies demonstrating no damaging effect of this variant are available. Details ▾Hide ▴
Evidence considered
  • No benign functional evidence identified.
Still missing
  • No functional studies available.
BS4 No non-segregation data are available for this variant. Details ▾Hide ▴
Evidence considered
  • No segregation data available.
Still missing
  • No family studies available.
BP1 SF3B1 missense variants are a known disease mechanism. De novo heterozygous missense variants in SF3B1 cause neurodevelopmental disorders (PMID:41577671), and somatic missense variants are common in hematologic malignancies. Truncating variants are not the sole mechanism of disease. Details ▾Hide ▴
Evidence considered
  • PMID:41577671 reports de novo SF3B1 missense variants causing neurodevelopmental disorders
  • missense is an established disease mechanism.
BP2 No observation of this variant in trans with a known dominant pathogenic variant is available. Details ▾Hide ▴
Evidence considered
  • No trans configuration data available.
Still missing
  • No phase data available.
BP4 In silico predictors do not support a benign interpretation. REVEL score of 0.562 predicts a deleterious effect, and SpliceAI predicts a possible splice impact (max delta = 0.44). Multiple predictors suggest a functional consequence. Details ▾Hide ▴
Evidence considered
  • REVEL 0.562 (deleterious).
  • SpliceAI max delta 0.44 (possible splice impact).
Sources
revelspliceai ↗
BP5 No alternate molecular basis for the observed phenotype has been identified in a case with this variant. Details ▾Hide ▴
Evidence considered
  • No alternate cause data available.
Still missing
  • No phenotype or alternate molecular data.
BP6 This variant has not been reported as benign by a reputable source. It is absent from ClinVar. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar.
Sources
clinvar ↗
PS5 This variant has not been previously classified as pathogenic by a reputable source. It is absent from ClinVar. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar
  • no established pathogenic classification.
Sources
clinvar ↗

Not assessed · 1 · no assessment recorded

PP2 HCI prior probability score is not available for SF3B1. Insufficient constraint metrics to determine whether SF3B1 has a low rate of benign missense variation, as required for PP2 application. Details ▾Hide ▴
Evidence considered
  • HCI prior not found for SF3B1
  • no gnomAD missense constraint Z-score available.
Still missing
  • Missense constraint data (Z-score
  • HCI prior) unavailable for SF3B1.
Not applicable · 2· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_012433.3:c.2263C>T is a missense variant (p.Pro755Ser) and does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. The ClinGen SVI PVS1 framework (PMC6185798) does not apply. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • not a null variant per PMC6185798 criteria.
Sources
pvs1_generic_framework ↗
BP7 N/ANM_012433.3:c.2263C>T is a missense variant (p.Pro755Ser), not a synonymous variant. BP7 applies only to synonymous variants without predicted splice impact. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • BP7 criteria are restricted to synonymous variants.

Identifiers

Gene
SF3B1
Transcript
NM_012433.3
Coding (HGVS c.)
NM_012433.3:c.2263C>T
Protein (HGVS p.)
NP_036565.2:p.(Pro755Ser)
GRCh38
chr2:197401849 G>A
GRCh37
chr2:198266573 G>A
COSMIC
COSV59230199

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 +65 bp
0.030
SpliceAI acceptor gainat -16 bp
0.440
SpliceAI donor lossat -107 bp
0.000
SpliceAI donor gainat +201 bp
0.000
Pangolin splice lossmagnitude shown
-0.020
Pangolin splice gain
0.140

Other predictors

REVEL
0.562
BayesDel
0.113

How the predictions were used

PP3 SupportingMultiple lines of in silico evidence support a deleterious effect. REVEL score of 0.562 exceeds the 0.5 threshold for deleterious prediction. SpliceAI predicts a possible splice impact with a max delta score of 0.44 (acceptor gain, DS_AG=0.44). Details ▾Hide ▴
Evidence considered
  • REVEL score 0.562 (deleterious prediction).
  • SpliceAI max delta 0.44 (acceptor gain DS_AG=0.44).
  • BayesDel score 0.112595 (below deleterious threshold
  • not contributory).
Sources
revelspliceai ↗bayesdel
BP4 In silico predictors do not support a benign interpretation. REVEL score of 0.562 predicts a deleterious effect, and SpliceAI predicts a possible splice impact (max delta = 0.44). Multiple predictors suggest a functional consequence. Details ▾Hide ▴
Evidence considered
  • REVEL 0.562 (deleterious).
  • SpliceAI max delta 0.44 (possible splice impact).
Sources
revelspliceai ↗
BP7 N/ANM_012433.3:c.2263C>T is a missense variant (p.Pro755Ser), not a synonymous variant. BP7 applies only to synonymous variants without predicted splice impact. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • BP7 criteria are restricted to synonymous variants.

Statement

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.44). REVEL score = 0.562. BayesDel score = 0.112595.

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 0.440 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 possible splice impact for this variant (max delta score = 0.44). REVEL score = 0.562. BayesDel score = 0.112595.

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; COSV59230199, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.