NM_012433.3:c.2263C>T

SF3B1 · NP_036565.2:p.(Pro755Ser) · NM_012433.3

GRCh37: chr2:198266573 G>A · GRCh38: chr2:197401849 G>A

Gene: SF3B1 Transcript: NM_012433.3

Final call

VUS

PM2 supporting PP3 supporting

Variant details

Gene

SF3B1

Transcript

NM_012433.3

Protein

NP_036565.2:p.(Pro755Ser)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	NM_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.	pvs1_generic_framework
PS1	Not met	No prior report of this exact nucleotide change as pathogenic in ClinVar or the literature.	clinvar
PS2	Not met	No de novo observation with confirmed maternity and paternity is available for this variant.
PS3	Not met	No variant-specific well-established functional studies were identified. OncoKB classifies this variant as Unknown Oncogenic Effect.	oncokb
PS4	Not met	No case-control studies comparing variant prevalence in affected individuals versus controls are available.
PS5	Not met	This variant has not been previously classified as pathogenic by a reputable source. It is absent from ClinVar.	clinvar
PM1	Not met	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.
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No pathogenic missense variant has been identified at residue Pro755 to serve as a same-residue comparator. Automated PM5 candidate harvesting returned no candidates.	pm5_candidates
PM6	Not met	No de novo observation (with or without confirmed parentage) is available for this variant.
PP1	Not met	No co-segregation data are available for this variant.
PP2	Not assessed	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.
PP3	Met	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).	revel spliceai bayesdel
PP4	Not met	No patient phenotype information is available for assessment of phenotypic specificity.
PP5	Not met	This variant has not been reported as pathogenic by a reputable source. It is absent from ClinVar.	clinvar
BA1	Not met	The variant is absent from gnomAD; the allele frequency does not exceed the 1% BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	The variant is absent from gnomAD; the allele frequency does not exceed the 0.3% BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Not met	No observations of this variant in healthy adults are available to assess BS2.
BS3	Not met	No well-established functional studies demonstrating no damaging effect of this variant are available.
BS4	Not met	No non-segregation data are available for this variant.
BP1	Not met	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.
BP2	Not met	No observation of this variant in trans with a known dominant pathogenic variant is available.
BP4	Not met	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.	revel spliceai
BP5	Not met	No alternate molecular basis for the observed phenotype has been identified in a case with this variant.
BP6	Not met	This variant has not been reported as benign by a reputable source. It is absent from ClinVar.	clinvar
BP7	N/A	NM_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.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.