NM_012433.4:c.1986C>A

SF3B1 · NP_036565.2:p.(His662Gln) · NM_012433.4

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

Gene: SF3B1 Transcript: NM_012433.4

Final call

VUS

PM2 supporting

Variant details

Gene

SF3B1

Transcript

NM_012433.4

Protein

NP_036565.2:p.(His662Gln)

gnomAD AF

4.337389412060669e-06 (v4.1)

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

The SF3B1 c.1986C>A (p.His662Gln) 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 is present at very low frequency in gnomAD v4.1 (7/1613874 alleles; AF 4.33739e-06; highest population AF 3.12354e-05), which is below the 0.1% rarity threshold used for PM2.

Published studies showed that SF3B1 pathway mutations and SF3B1 disruption can alter RNA splicing, growth, and erythroid differentiation, but a well-established assay specific to p.His662Gln was not identified.

In silico results were mixed, with REVEL 0.628 and BayesDel 0.0218, while SpliceAI predicted no significant splice impact with a maximum delta score of 0.07, so computational evidence did not 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	Gene-level review supports considering generic PVS1 for true loss-of-function variants in SF3B1, but NM_012433.4:c.1986C>A is a missense substitution and does not fall within the nonsense, frameshift, or canonical +/-1,2 splice categories used by the generic PVS1 framework.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	Not assessed	No pathogenic or likely pathogenic comparator producing the same amino acid change was identified in the available sources, so PS1 could not be established.	clinvar
PS2	Not assessed	No confirmed de novo occurrence with established maternity and paternity was identified for this variant.
PS3	Not assessed	Published studies showed that SF3B1 pathway mutations and SF3B1 disruption can alter RNA splicing and hematopoietic function, but no well-established functional assay specific to p.(His662Gln) demonstrating a damaging effect was identified.	PMID:21909114 PMID:25428262 oncokb
PS4	Not met	This variant has been observed in somatic cancer resources and is absent from ClinVar, but no germline case-control study or affected-individual enrichment dataset for this exact variant was identified, so PS4 is not met.	oncokb clinvar
PM1	Not met	Available hotspot review did not confirm that p.(His662Gln) lies in a statistically significant hotspot or a well-established critical region without benign variation, so PM1 is not met.	hotspots
PM2	Met	This variant is absent from gnomAD v2.1 and present at very low frequency in gnomAD v4.1 (7/1613874 alleles; AF 4.33739e-06; highest population AF 3.12354e-05 in Finnish individuals; grpmax FAF 6.8e-07), which is below the 0.1% rarity threshold and supports PM2.	gnomad_v2 gnomad_v4
PM3	N/A	No evidence was identified for this variant in trans with a pathogenic variant in a recessive disease context, so PM3 does not apply.
PM4	N/A	This is a missense substitution and does not cause a protein length change, so PM4 does not apply.
PM5	N/A	Classic same-residue PM5 semantics could not be confirmed safely for this gene/framework, and no validated same-residue pathogenic or likely pathogenic comparator was established for use here.	pm5_candidates
PM6	Not assessed	No assumed de novo occurrence without parental confirmation was identified for this variant.
PP1	Not assessed	No segregation data were identified for this variant in affected family members.
PP2	Not assessed	Available evidence did not establish a gene-specific missense-constraint rule suitable to apply PP2 for this variant.
PP3	Not met	Computational evidence is not sufficiently concordant to support PP3. REVEL was 0.628 and BayesDel was 0.0218, while SpliceAI predicted no significant splice effect with a maximum delta score of 0.07.	revel bayesdel spliceai
PP4	Not assessed	No phenotype-specific clinical information was provided to determine whether the presentation is highly specific for an SF3B1-related disorder.
PP5	N/A	No reputable external pathogenic classification for this variant was identified in the reviewed germline sources.	clinvar
BA1	Not met	Population frequency does not meet the benign stand-alone threshold. The highest observed population frequency in gnomAD v4.1 was 3.12354e-05, which is far below the 1% threshold.	gnomad_v4
BS1	Not met	Population frequency does not meet the benign strong threshold. The highest observed population frequency in gnomAD v4.1 was 3.12354e-05, which is below the 0.3% threshold.	gnomad_v4
BS2	Not assessed	Available population data do not establish observation of this variant in healthy individuals in a manner sufficient to apply BS2.	gnomad_v4
BS3	Not assessed	Published studies showed functional consequences of SF3B1 disruption and broader SF3B1 pathway mutations, but no well-established assay specific to p.(His662Gln) demonstrating normal function was identified.	PMID:21909114 PMID:25428262 oncokb
BS4	Not assessed	No informative family data were identified showing lack of segregation with disease.
BP1	N/A	BP1 does not apply because the available evidence does not indicate a disease mechanism in which truncating variants predominate and missense variation is generally expected to be benign for SF3B1.	pvs1_gene_context
BP2	Not assessed	No phase data or alternate molecular diagnosis information were identified to support BP2.
BP3	Not assessed	No evidence was identified that this missense change lies in a repetitive region without known function.
BP4	Not met	Computational evidence does not support a benign interpretation. REVEL was 0.628 and BayesDel was 0.0218, and SpliceAI predicted no significant splice effect with a maximum delta score of 0.07; these results are not sufficient to support BP4.	revel bayesdel spliceai
BP5	Not assessed	No alternate molecular cause was provided that would explain the phenotype independently of this variant.
BP6	N/A	No reputable external benign classification for this variant was identified in the reviewed germline sources.	clinvar
BP7	N/A	BP7 does not apply because this variant is missense rather than synonymous or intronic outside the splice region.

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