Variant classification summary

NM_012433.4:c.1874G>A

SF3B1 · NP_036565.2:p.(Arg625His) · NM_012433.4

GRCh37: chr2:198267483 C>T · GRCh38: chr2:197402759 C>T

Gene: SF3B1 Transcript: NM_012433.4

Final call

VUS

PM1 moderate PM2 supporting PP3 moderate

Variant details

Gene

SF3B1

Transcript

NM_012433.4

Protein

NP_036565.2:p.(Arg625His)

gnomAD AF

6.195740799944486e-07 (v4.1)

ClinVar

Likely pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM1 moderate: R625 is a recurrent statistically significant hotspot and the allele is ultra-rare.

2

PM2 supporting: gnomAD v4.1 AF is 6.20e-7 (1/1,614,012 alleles; 0 homozygotes).

3

PP3 moderate: REVEL 0.875 exceeds the generic missense threshold.

4

VUS: two moderate plus one supporting pathogenic-side criteria do not satisfy a generic ACMG/AMP classification rule.

Final determination: Under the generic ACMG/AMP 2015 fallback, two moderate and one supporting pathogenic-side criteria do not meet any Pathogenic or Likely Pathogenic combination, while no benign rule is satisfied, so the final call is VUS.

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: p.Arg625His is reported, but no independently established pathogenic comparator is available for the PS1 requirement.	PMID:23861464 clinvar
PS2	Not assessed	Not assessed: no proband-level germline parental testing or family-history evidence confirms de novo occurrence with both maternity and paternity confirmed.	clinvar
PS3	Not assessed	Not assessed: p.R625H was found in 9 uveal melanomas, but variant-specific, replicated, and clinically validated functional evidence was not established.	PMID:23861464
PS4	Not assessed	Not assessed: p.R625H was reported in 9 uveal melanoma tumors, but no exact-variant control count was provided to calculate OR/RR >5.0 with a 95% CI excluding 1.0.	PMID:23861464
PM1	Met	Met at moderate strength: R625 is a statistically significant hotspot with four reported substitutions, while gnomAD v4.1 shows only 1/1,614,012 alleles.	hotspots PMID:23861464 gnomad_v4
PM2	Met	Met at supporting: gnomAD v4.1 AF is 6.20e-7 (1/1,614,012 alleles; 0 homozygotes), below the 0.0001 PM2 threshold.	gnomad_v2 gnomad_v4 PMID:25741868
PM3	Not assessed	Not assessed: no recessive inheritance context or parent/offspring testing establishes this variant in trans with a pathogenic allele.	PMID:23861464 PMID:25741868 clinvar
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: R625C, R625P, and R625L are reported, but none is established as pathogenic in the available evidence.	PMID:23861464 hotspots cosmic
PM6	Not assessed	Not assessed: no proband-level germline evidence shows assumed de novo occurrence without confirmed maternity and paternity testing.	clinvar
PP1	Not assessed	Not assessed: zero affected relatives or informative meioses are documented to demonstrate co-segregation with disease.	clinvar
PP2	Not assessed	Not assessed: recurrent SF3B1 missense disease evidence is present, but no defined evidence establishes both low benign-missense variation and the required gene-level mechanism.	PMID:23861464 gnomad_v4
PP3	Met	Met at moderate strength: REVEL 0.875 exceeds the generic PP3 moderate threshold of 0.773 for this missense variant.	revel PMID:25741868
PP4	Not assessed	Not assessed: no patient phenotype or family-history description is available to determine whether the presentation is highly specific for a single-gene disease.
PP5	Not met	Not met: ClinVar has a single-submitter Likely pathogenic label, but PP5 requires a reputable source and this record has zero expert-panel submissions.	clinvar
BA1	Not assessed	Not assessed: total AF is 6.20e-7 versus the 0.05 BA1 threshold, but the required grpmax FAF is unavailable.	gnomad_v4
BS1	Not assessed	Not assessed: total AF is 6.20e-7 versus the 0.01 default, but grpmax FAF and a disease-specific maximum credible AF are unavailable.	gnomad_v4
BS2	Not assessed	Not assessed: gnomAD shows 0 homozygotes and 1 allele, but provides no individual-level healthy-adult or phenotype information.	gnomad_v4
BS3	Not assessed	Not assessed: no well-established assay showed that p.R625H has no damaging effect on SF3B1 protein function or splicing.	PMID:23861464
BS4	Not assessed	Not assessed: no affected relatives are documented to lack the variant, so lack of segregation cannot be evaluated.	clinvar
BP1	Not assessed	Not assessed: available SF3B1 evidence shows recurrent missense mutations, but does not establish a gene-wide predominance of truncating disease variants.	PMID:23861464
BP2	Not assessed	Not assessed: no documented pathogenic partner allele or validated cis/trans phase is available for this somatic SF3B1 variant.	PMID:23861464 PMID:25741868 clinvar
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 0.875 is above the generic BP4 supporting threshold of 0.29 for this missense variant.	revel PMID:25741868
BP5	Not assessed	Not assessed: no affected case is documented with this variant and an established alternate molecular basis for disease.
BP6	Not met	Not met: the exact ClinVar record is a single-submitter Likely pathogenic assertion, not an expert-panel benign or likely benign classification.	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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