NM_012433.2:c.1876A>G

SF3B1 · NP_036565.2:p.(Asn626Asp) · NM_012433.2

GRCh37: chr2:198267481 T>C · GRCh38: chr2:197402757 T>C

Gene: SF3B1 Transcript: NM_012433.2

Final call

VUS

PM2 supporting

Variant details

Gene

SF3B1

Transcript

NM_012433.2

Protein

NP_036565.2:p.(Asn626Asp)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

The SF3B1 c.1876A>G (p.Asn626Asp; p.N626D) variant has been curated as a somatic cancer variant in OncoKB and has not been reported in ClinVar.

This variant is rare in population databases, with gnomAD v2.1 showing 1/251158 alleles (0.00040%) and gnomAD v4.1 showing 8/1613994 alleles (0.00050%; grpmax FAF 0.000124%), which is below the 0.1% PM2 threshold.

In silico results are mixed: SpliceAI predicts no significant splice impact (maximum delta score 0.08), while REVEL is 0.60 and BayesDel is -0.0733292, so computational evidence does not independently support PP3 or BP4.

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, not a nonsense, frameshift, or canonical +/-1,2 splice variant, so the generic PVS1 loss-of-function framework does not apply.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	Not assessed	No evidence was identified showing that a different nucleotide change produces the same amino acid substitution with an established pathogenic interpretation.
PS2	Not assessed	No confirmed de novo occurrence with verified maternity and paternity was identified.	clinvar
PS3	Not assessed	No published functional study specific to p.(Asn626Asp) was identified that demonstrates a damaging effect using a validated assay.	oncokb
PS4	Not assessed	Somatic database curation suggests this variant has been observed in cancers, but no germline case-control or affected-versus-control enrichment data were identified for this variant.	oncokb clinvar
PM1	Not assessed	A hotspot signal was suggested, but the reviewed hotspot evidence for codon 626 was marked uncertain and did not confirm that this exact residue is an established mutational hotspot or critical benign-variant-depleted region.	hotspots oncokb
PM2	Met	Population frequency is below the non-VCEP PM2 threshold of 0.1% in gnomAD v2.1 (0.00040%, 1/251158 alleles) and gnomAD v4.1 (0.00050%, 8/1613994 alleles; grpmax FAF 0.000124%), supporting rarity in population databases.	gnomad_v2 gnomad_v4
PM3	Not assessed	No evidence was identified showing this variant in trans with a pathogenic variant for a recessive disorder.
PM4	N/A	This variant is a missense substitution and does not create a protein length change or in-frame exon-level alteration.
PM5	Not assessed	No evidence was identified showing a different pathogenic missense change at the same codon that would support PM5.
PM6	Not assessed	No presumed de novo occurrence without confirmed parentage was identified.	clinvar
PP1	Not assessed	No segregation data were identified to show co-segregation with disease in affected family members.	clinvar
PP2	Not assessed	Available evidence shows SF3B1 missense variation can be clinically relevant, but no gene-specific missense-rate framework was identified to support applying PP2 in this case.	oncokb
PP3	Not met	Computational evidence is mixed. REVEL is 0.60, BayesDel is -0.0733292, and SpliceAI predicts no significant splice effect with a maximum delta score of 0.08, so in silico results do not consistently support a deleterious effect.	revel bayesdel spliceai
PP4	Not assessed	No phenotype information was provided that would allow assessment of whether the clinical presentation is highly specific for an SF3B1-related disorder.
PP5	Not assessed	No qualifying pathogenic classification from a germline clinical database or other accepted external clinical source was identified for this variant.	clinvar
BA1	Not met	Population frequency does not meet the benign stand-alone BA1 threshold of greater than 1%. The highest observed gnomAD v4.1 population frequency is 0.00320% and overall frequency is 0.00050%.	gnomad_v4 gnomad_v2
BS1	Not met	Population frequency does not meet the benign BS1 threshold of greater than 0.3%. The highest observed gnomAD v4.1 population frequency is 0.00320%, which is well below this threshold.	gnomad_v4 gnomad_v2
BS2	Not assessed	The variant is very rare in population databases and no evidence was identified showing observation in healthy adults at a frequency sufficient to support BS2.	gnomad_v2 gnomad_v4
BS3	Not assessed	No published functional study specific to p.(Asn626Asp) was identified showing normal protein function or a benign effect.	oncokb
BS4	Not assessed	No family data were identified showing lack of segregation between this variant and disease.	clinvar
BP1	N/A	This is a missense variant in a gene with established clinically relevant missense variation, so BP1 does not fit this variant-gene context.	oncokb
BP2	Not assessed	No case-level phase information was identified to determine whether this variant occurs in trans with a pathogenic variant or in cis with another variant.
BP3	Not assessed	No evidence was identified showing that this missense change is located in a repetitive region without known function.
BP4	Not met	Computational evidence does not consistently support a benign effect. SpliceAI predicts no significant splice impact (max delta 0.08), but REVEL is 0.60 and BayesDel is -0.0733292, so the overall in silico profile is mixed.	spliceai revel bayesdel
BP5	Not assessed	No alternate molecular diagnosis or variant explanation was provided that would account for the phenotype independently of this variant.
BP6	Not assessed	No qualifying benign classification from a germline clinical database or other accepted external clinical source was identified for this variant.	clinvar
BP7	N/A	BP7 is for synonymous or certain intronic variants, and this variant is a missense substitution.

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.