Variant classification summary

NM_012433.3:c.2469G>A

SF3B1 · NP_036565.2:p.(Met823Ile) · NM_012433.3

GRCh37: chr2:198266151 C>T · GRCh38: chr2:197401427 C>T

Gene: SF3B1 Transcript: NM_012433.3

Final call

VUS

PM2 moderate PP2 supporting

Variant details

Gene

SF3B1

Transcript

NM_012433.3

Protein

NP_036565.2:p.(Met823Ile)

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Moderate): the variant is absent from population controls in gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0.

2

PP2 (Supporting): missense is an established germline disease mechanism for SF3B1, seen in 17 of 26 reported patients with SF3B1-related neurodevelopmental disorder.

3

Combined, PM2 (Moderate) plus PP2 (Supporting) does not satisfy any ACMG/AMP 2015 Pathogenic, Likely Pathogenic, Benign, or Likely Benign combination, so the variant is classified as VUS.

Final determination: Generic ACMG/AMP 2015 fallback rules: with only PM2 (moderate) and PP2 (supporting) met, no Pathogenic, Likely Pathogenic, Benign, or Likely Benign combination threshold is reached, 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	Not applicable: this missense substitution does not trigger a null-variant mechanism such as nonsense-mediated decay.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no established-pathogenic p.Met823Ile allele from a different nucleotide change exists; the variant is absent from ClinVar.	clinvar
PS2	Not assessed	Not assessed: no proband phenotype or parental genotype data were available to establish a confirmed de novo occurrence.
PS3	Not assessed	Not assessed: no validated functional assay data for p.Met823Ile were available.
PS4	Not assessed	Not assessed: no case-control or enrichment data for this variant were available.
PM1	Not met	Not met: residue 823 shows no statistically significant hotspot signal in cancerhotspots.org and no somatic recurrence in COSMIC.
PM2	Met	Met (Moderate): absent from all queried population controls, including gnomAD v2.1, v4.1, and gnomAD-Canada v1.0.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	Not assessed: no affected-proband observations with a pathogenic variant in trans, or recessive disease context, were available.	generic_acmg_combination_rules
PM4	N/A	Not applicable: PM4 applies only to in-frame insertions/deletions or stop-loss length changes; this is a missense substitution.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no different missense change at residue 823 previously established as pathogenic was identified.	pm5_candidates
PM6	Not assessed	Not assessed: no de novo occurrence or parental testing was reported.
PP1	Not assessed	Not assessed: no familial co-segregation data were available.
PP2	Met	Met (Supporting): missense is an established germline disease mechanism for SF3B1, documented in 17 of 26 reported patients.	pvs1_gene_context
PP3	Not met	Not met: REVEL score 0.571 falls below the >=0.644 PP3_Supporting threshold, in the indeterminate zone.	revel spliceai
PP4	Not assessed	Not assessed: no phenotype data for a carrier of this variant were available.
PP5	Not met	Not met: no exact-variant ClinVar record exists, so no expert-panel Pathogenic or Likely pathogenic assertion supports PP5.	clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, so no allele frequency reaches the BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: the variant is absent from all queried population datasets, so it cannot exceed the expected benign frequency.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	Not assessed: no observations in well-phenotyped unaffected individuals were provided.
BS3	Not assessed	Not assessed: no functional assay data demonstrating normal protein function were available.
BS4	Not assessed	Not assessed: no unaffected variant-positive relatives or other non-segregation observations were provided.
BP1	Not met	Not met: missense is an established disease mechanism for SF3B1, so the truncation-only premise of BP1 does not apply.	pvs1_gene_context
BP2	Not assessed	Not assessed: no co-occurring pathogenic variant or phase evidence was available.	generic_acmg_combination_rules
BP3	N/A	Not applicable: BP3 applies only to in-frame insertions/deletions in repetitive regions; this is a missense substitution.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: REVEL score 0.571 is well above the <=0.290 BP4_Supporting threshold, in the indeterminate zone.	revel spliceai
BP5	Not assessed	Not assessed: no alternate molecular diagnosis could be evaluated from the available data.
BP6	Not met	Not met: no exact-variant ClinVar record exists, so no expert-panel Benign or Likely benign assertion supports BP6.	clinvar
BP7	N/A	Not applicable: BP7 applies only to synonymous variants; this missense substitution alters the encoded protein.	generic_acmg_combination_rules

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