Variant classification summary

NM_012433.3:c.1873C>A

SF3B1 · NP_036565.2:p.(Arg625Ser) · NM_012433.3

GRCh37: chr2:198267484 G>T · GRCh38: chr2:197402760 G>T

Gene: SF3B1 Transcript: NM_012433.3

Final call

VUS

PM1 moderate PM2 moderate

Variant details

Gene

SF3B1

Transcript

NM_012433.3

Protein

NP_036565.2:p.(Arg625Ser)

gnomAD AF

6.196017200143747e-07 (v4.1)

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The variant c.1873C>A (p.Arg625Ser) in SF3B1 alters a residue in a statistically significant mutational hotspot, meeting PM1 at moderate strength.

2

The variant is extremely rare in population databases, present at an allele frequency of 6.2e-07 (1/1,613,940 alleles) in gnomAD v4.1 and absent from gnomAD v2.1, meeting PM2 at moderate strength.

3

Computational evidence is discordant: REVEL predicts a deleterious effect (0.806) but BayesDel predicts a benign effect (0.235), and SpliceAI predicts no splicing impact (delta 0.12). PP3 and BP4 are not met.

4

No variant-specific publications, ClinVar classifications, de novo reports, functional studies, or segregation data are available. Multiple criteria (PS2, PS3, PS4, PM6, PP1, PP4, BS2, BS3, BS4, BP2, BP5) could not be assessed.

5

The variant is absent from ClinVar and has not been classified by any germline reputable source; PP5 and BP6 are not met.

6

Two moderate pathogenic criteria (PM1, PM2) are met with zero benign criteria met. This falls short of the Likely Pathogenic threshold (≥3 moderate, or ≥2 moderate + ≥2 supporting, or ≥1 strong + ≥1 moderate) per ACMG/AMP 2015 combination rules. The variant is classified as a Variant of Uncertain Significance (VUS).

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	This is a missense variant (c.1873C>A, p.Arg625Ser) and does not fall into any PVS1 null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice consensus). The PVS1 variant assessment confirms this variant is not eligible for generic PVS1 framework application.	pvs1_variant_assessment pvs1_generic_framework
PS1	N/A	No known pathogenic variant with the same amino acid change (Arg625Ser) has been identified. This variant is absent from ClinVar, and no same-residue pathogenic comparators were found.	clinvar pm5_candidates
PS2	Not assessed	No de novo reports with confirmed maternity and paternity are available for this variant. No publications were identified in the literature pass.
PS3	Not assessed	No variant-specific well-established functional studies are available. OncoKB classifies this variant as 'Likely Oncogenic' in a somatic context and COSMIC reports three somatic occurrences (COSV59228873), but no publications with experimental functional evidence were identified for independent verification.	oncokb
PS4	Not assessed	No case-control or variant prevalence data in affected versus unaffected individuals are available. The variant is absent from ClinVar and no publications with patient counts were identified.
PS5	N/A	No alternate pathogenic missense variant at the same residue (Arg625) has been identified in ClinVar or other sources. PM5 candidate harvesting found no same-residue comparators.	pm5_candidates clinvar
PM1	Met	The variant alters residue Arg625, which lies in a statistically significant mutational hotspot in SF3B1. SF3B1 hotspot mutations cluster in the HEAT domain, and codon 625 is a well-established recurrent mutation site.
PM2	Met	This variant is extremely rare in population databases. It is absent from gnomAD v2.1 and present in gnomAD v4.1 at an allele frequency of 6.2e-07 (1/1,613,940 alleles, 0 homozygotes), with the single observation in the South Asian subpopulation (AF 1.1e-05). This frequency is well below the 0.1% PM2 threshold for non-VCEP assessment.	gnomad_v4 gnomad_v2
PM5	N/A	No pathogenic missense comparator at the same residue (Arg625) was identified. PM5 candidate harvesting found zero same-residue candidates, and ClinVar lacks entries at this position.	pm5_candidates clinvar
PM6	Not assessed	No de novo reports (confirmed or unconfirmed parentage) are available for this variant. No publications were identified in the literature pass.
PP1	Not assessed	No co-segregation data in affected families is available for this variant. No publications with family studies were identified.
PP2	Not assessed	SF3B1 is a gene where missense variants are a known disease mechanism (germline de novo missense variants cause neurodevelopmental disorders per PMID:41577671). However, insufficient data on the gene's benign missense variation rate (e.g., missense Z-score or constraint metrics) are available to formally apply PP2.
PP3	Not met	Multiple lines of computational evidence do not consistently support a deleterious effect. REVEL score of 0.806 supports pathogenicity (above 0.75 threshold), but BayesDel score of 0.235 is discordant and supports a benign interpretation. SpliceAI delta score of 0.12 predicts no significant splice impact. Only one of three in silico tools supports a deleterious effect.	revel bayesdel spliceai
PP4	Not assessed	No patient phenotype or clinical data are available for this variant. The variant is absent from ClinVar and no case reports were identified.
PP5	Not met	This variant is absent from ClinVar and has not been classified by any reputable source. OncoKB classifies it as 'Likely Oncogenic,' but this is a somatic designation and does not satisfy PP5 requirements for a germline source.	clinvar oncokb
BA1	Not met	The allele frequency of this variant in gnomAD v4.1 is 6.2e-07 (0.000062%), which is far below the 1% BA1 threshold. This variant is not a common polymorphism.	gnomad_v4
BS1	Not met	The allele frequency of this variant in gnomAD v4.1 is 6.2e-07 (0.000062%), which is far below the 0.3% BS1 threshold for non-VCEP assessment. The variant is extremely rare in the general population.	gnomad_v4
BS2	Not assessed	No data on observation of this variant in healthy adult controls are available. The single gnomAD v4.1 observation lacks phenotypic annotation.
BS3	Not assessed	No variant-specific well-established functional studies demonstrating a benign effect are available. No publications were identified in the literature pass.
BS4	Not assessed	No family segregation data are available to evaluate lack of segregation with disease. No publications with family studies were identified.
BP1	N/A	SF3B1 missense variants are a known disease mechanism; germline de novo missense variants cause neurodevelopmental disorders (PMID:41577671). BP1 is reserved for genes where primarily truncating variants cause disease, which is not the case for SF3B1.	pvs1_gene_context
BP2	Not assessed	No data on observation of this variant in trans with a pathogenic variant are available. The variant has not been reported in any clinical or research context.
BP4	Not met	Multiple lines of computational evidence do not consistently suggest no impact on the gene product. REVEL score of 0.806 supports a deleterious effect, contradicting a benign prediction. BayesDel score of 0.235 is in the benign range, but SpliceAI delta score of 0.12 is uninformative. The evidence does not meet the threshold for multiple lines all pointing to no impact.	revel bayesdel spliceai
BP5	Not assessed	No data are available on cases harboring this variant with an alternate molecular basis for disease. No publications or clinical reports were identified.
BP6	Not met	This variant is absent from ClinVar; no reputable source has reported it as benign. BP6 requires a reputable source to classify the variant as benign.	clinvar
BP7	N/A	This is a missense variant (c.1873C>A, p.Arg625Ser), not a synonymous or intronic variant. BP7 applies only to synonymous variants with no predicted splice impact.
BP3	N/A	This is a substitution variant; BP3 applies to in-frame insertions/deletions in repetitive regions.
PM3	N/A	SF3B1-associated disorders follow autosomal dominant inheritance with de novo heterozygous variants; PM3 is for recessive disorders.
PM4	N/A	This is a missense substitution; PM4 applies to non-repeat in-frame deletions/insertions and stop-loss variants.

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