Variant classification summary

NM_012433.4:c.2098A>G

SF3B1 · NP_036565.2:p.(Lys700Glu) · NM_012433.4

GRCh37: chr2:198266834 T>C · GRCh38: chr2:197402110 T>C

Gene: SF3B1 Transcript: NM_012433.4

Final call

Likely Pathogenic

PS3 strong PM1 moderate PM2 supporting

Variant details

Gene

SF3B1

Transcript

NM_012433.4

Protein

NP_036565.2:p.(Lys700Glu)

gnomAD AF

4.4885262048887535e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Likely Pathogenic: PS3 strong from variant-specific studies showing aberrant splicing and partial SUGP1 rescue.

2

Likely Pathogenic: PM1 moderate because K700E is a recurrent statistically significant SF3B1 hotspot.

3

Likely Pathogenic: PM2 supporting because gnomAD frequency is below 0.0001 with zero homozygotes.

Final determination: Under the generic ACMG/AMP 2015 fallback, 1 strong pathogenic criterion plus 1 moderate pathogenic criterion plus 1 supporting pathogenic criterion supports Likely Pathogenic.

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	Not applicable: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: K700E is a recurrent somatic hotspot, but no validated previously established pathogenic comparator is supplied for PS1.	clinvar PMID:25424858 cosmic
PS2	Not assessed	Not assessed: no documented maternity and paternity confirmation or family-history data establish a de novo occurrence.
PS3	Met	Met, strong: K700E caused aberrant 3' splice-site usage in engineered and endogenous models, with partial rescue by SUGP1 overexpression.	PMID:27818134 PMID:31474574
PS4	Not assessed	Not assessed: gnomAD v4.1 gives 72/1,604,090 control alleles, but no affected-case count exists to calculate the required OR/RR >5.0 and 95% CI excluding 1.0.	gnomad_v4 PMID:25424858
PM1	Met	Met: K700E is at a statistically significant recurrent hotspot, with COSMIC reporting 811 occurrences and a study identifying codon 700 as a recurrent hotspot.	hotspots cosmic PMID:25424858
PM2	Met	Met at supporting strength: gnomAD AF is 4.49e-05 in v4.1, below the <=0.0001 PM2 threshold, with zero homozygotes.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no affected-proband observation or parental testing demonstrates this variant in trans with a pathogenic allele for a recessive disorder.	PMID:27818134
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no different pathogenic missense comparator at Lys700 is documented, while the reported K700E observations are the same amino-acid change.	pm5_candidates PMID:25424858 cosmic
PM6	Not assessed	Not assessed: no case-level evidence shows an assumed de novo variant without maternity and paternity confirmation.
PP1	Not assessed	Not assessed: no affected relatives or informative meioses are documented to evaluate co-segregation.
PP2	Not assessed	Not assessed: gene-wide benign missense depletion and a qualifying common missense disease mechanism are not both demonstrated by the supplied evidence.	gnomad_v4 PMID:27818134 PMID:31474574
PP3	Not met	Not met: REVEL 0.619 is below the generic supporting PP3 threshold of 0.644 for this missense variant.	revel
PP4	Not assessed	Not assessed: the available records provide no patient phenotype or family history that is highly specific for a single-gene disease.
PP5	Not met	Not met: no exact-variant ClinVar expert-panel Pathogenic/Likely pathogenic classification is present; available submissions are non-expert and conflicting.	clinvar
BA1	Not met	Not met: gnomAD maximum observed frequency is 2.97e-04, far below the 0.05 BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: highest reported gnomAD ancestry frequency is 2.97e-04, below the generic 0.01 BS1 default.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD shows zero homozygotes but does not document a healthy adult carrier, age, phenotype, or full early-age penetrance.	gnomad_v2 gnomad_v4
BS3	Not met	Not met: K700E increased aberrant splicing and impaired SUGP1 association rather than showing no damaging effect on SF3B1 function.	PMID:27818134 PMID:31474574
BS4	Not assessed	Not assessed: no affected family members with documented variant status are available to evaluate lack of segregation.
BP1	Not met	Not met: SF3B1 has recurrent disease-associated missense biology, including K700E splicing defects, rather than a primarily truncating disease mechanism.	PMID:25424858 PMID:27818134 PMID:31474574
BP2	Not assessed	Not assessed: no phase-resolved observation shows this variant in trans or cis with a pathogenic variant under the BP2 inheritance conditions.	PMID:27818134
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: REVEL 0.619 exceeds the generic supporting BP4 threshold of 0.29, leaving no benign computational support.	revel
BP5	Not assessed	Not assessed: no case is documented with this variant plus an alternate molecular basis for the disease.
BP6	Not met	Not met: ClinVar has no exact-variant expert-panel Benign/Likely benign classification, and the available record is conflicting.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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