NM_012433.2:c.1986C>A

SF3B1 · NP_036565.2:p.(His662Gln) · NM_012433.2

GRCh37: chr2:198267371 G>T · GRCh38: chr2:197402647 G>T

Gene: SF3B1 Transcript: NM_012433.2

Final call

VUS

PM2 moderate PP3 supporting

Variant details

Gene

SF3B1

Transcript

NM_012433.2

Protein

NP_036565.2:p.(His662Gln)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

The SF3B1 NM_012433.2:c.1986C>A (NP_036565.2:p.(His662Gln), p.(H662Q)) variant has been observed in somatic cancer curation resources and has not been reported in ClinVar.

This variant is absent from gnomAD v2.1 and remains very rare in gnomAD v4.1 at 7/1613874 alleles (0.00043%), with the highest observed population frequency of 0.00312% in Finnish individuals, which is below the 0.1% PM2 rarity threshold.

Published SF3B1 functional literature was identified for review, but the available evidence did not provide a validated assay directly testing p.(His662Gln), so functional criteria were not applied.

Computational evidence supports a deleterious missense effect, with REVEL 0.628 and BayesDel 0.0218, while SpliceAI shows a low maximum delta score of 0.07 and does not support a splice-altering effect.

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 or 2 splice-site variant, so the generic PVS1 null-variant framework does not apply.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	Not assessed	No evidence was identified that another nucleotide change produces the same amino acid substitution with an established pathogenic classification, so PS1 was not assessed.	clinvar
PS2	Not assessed	No confirmed de novo occurrence with parental testing was identified for this variant, so PS2 was not assessed.	clinvar
PS3	Not assessed	Published functional literature relevant to SF3B1 was identified, but the available evidence did not provide a validated functional assay directly testing p.(His662Gln), so PS3 was not applied.	oncokb PMID:21909114 PMID:25428262
PS4	Not met	This variant has been observed in somatic cancer resources, but no germline case-control or affected-versus-control enrichment data for p.(His662Gln) were identified, so PS4 is not met.	oncokb clinvar PMID:21909114 PMID:25428262
PM1	Not met	Available evidence does not support that this variant lies in a statistically established mutational hotspot or a well-defined critical functional domain without benign variation, so PM1 is not met.	hotspots oncokb PMID:21909114 PMID:25428262
PM2	Met	This variant is absent from gnomAD v2.1 (0/251370 alleles, 0.00000%) and is present at very low frequency in gnomAD v4.1 (7/1613874 alleles, 0.00043%; highest population frequency 0.00312% in Finnish individuals), which is below the 0.1% PM2 threshold and supports rarity.	gnomad_v2 gnomad_v4
PM3	Not assessed	No evidence was identified that this variant was observed in trans with a pathogenic variant in a recessive disorder context, so PM3 was not assessed.	clinvar
PM4	N/A	This variant is a missense substitution and does not cause a protein length change, so PM4 does not apply.
PM5	Not assessed	No evidence was identified that a different missense change at codon 662 has an established pathogenic classification, so PM5 was not assessed.	clinvar
PM6	Not assessed	No assumed de novo occurrence without full parental confirmation was identified for this variant, so PM6 was not assessed.	clinvar
PP1	Not assessed	No segregation data were identified for this variant in affected family members, so PP1 was not assessed.	clinvar
PP2	Not assessed	Available evidence does not establish a gene-specific missense-constraint rule for SF3B1 that would justify PP2, so this criterion was not assessed.
PP3	Met	Multiple computational predictors support a deleterious missense effect: REVEL is 0.628, above a supportive threshold of 0.6, and BayesDel is 0.0218, above 0; SpliceAI shows a maximum delta score of 0.07, below 0.2, which does not support a splice effect but does not negate protein-level deleterious prediction.	revel bayesdel spliceai
PP4	Not assessed	No patient phenotype or disease-specific clinical presentation was provided that is highly specific for a single-gene disorder caused by SF3B1, so PP4 was not assessed.
PP5	Not assessed	No germline reputable-source pathogenic classification for this variant was identified, so PP5 was not assessed.	clinvar
BA1	Not met	The highest observed population frequency is 0.00312% in gnomAD v4.1, which is well below the 1% BA1 threshold, so BA1 is not met.	gnomad_v4
BS1	Not met	The highest observed population frequency is 0.00312% in gnomAD v4.1, which is below the 0.3% BS1 threshold, so BS1 is not met.	gnomad_v4
BS2	Not assessed	This variant is very rare in population databases and no evidence was identified showing occurrence in healthy adults at a frequency sufficient for BS2, so BS2 was not assessed.	gnomad_v4
BS3	Not assessed	No well-established functional study was identified showing normal function for p.(His662Gln), so BS3 was not applied.	oncokb PMID:21909114 PMID:25428262
BS4	Not assessed	No non-segregation data were identified for this variant in affected families, so BS4 was not assessed.	clinvar
BP1	N/A	BP1 does not apply because SF3B1 is not a gene in which only truncating variants are known to cause disease while missense variation is generally benign.	pvs1_gene_context
BP2	Not assessed	No evidence was identified that this variant occurs in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant, so BP2 was not assessed.	clinvar
BP3	Not assessed	No evidence was identified that this variant lies in a repetitive region without known function, so BP3 was not assessed.
BP4	Not met	Available computational evidence does not support a benign effect: REVEL is 0.628 and BayesDel is 0.0218, both consistent with deleterious missense prediction, while SpliceAI is 0.07 and only argues against a splice effect.	revel bayesdel spliceai
BP5	Not assessed	No alternate molecular diagnosis or independent cause for disease was provided, so BP5 was not assessed.
BP6	Not assessed	No reputable benign classification for this variant was identified, so BP6 was not assessed.	clinvar
BP7	N/A	BP7 does not apply because this variant is missense rather than a synonymous or deep intronic change.

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