NM_012433.2:c.1866G>T

SF3B1 · NP_036565.2:p.(Glu622Asp) · NM_012433.2

GRCh37: chr2:198267491 C>A · GRCh38: chr2:197402767 C>A

Gene: SF3B1 Transcript: NM_012433.2

Final call

VUS

PM2 moderate

Variant details

Gene

SF3B1

Transcript

NM_012433.2

Protein

NP_036565.2:p.(Glu622Asp)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

The SF3B1 c.1866G>T (p.Glu622Asp; p.E622D) variant has been observed in somatic cancer resources and has not been reported in ClinVar.

In population databases, this variant is absent from gnomAD v2.1 and is present at very low frequency in gnomAD v4.1 (AF 2.478382310298422e-06, 4/1613956 alleles), which is below the default PM2 threshold of 0.1%.

Published studies show that disease-associated SF3B1 missense variants cluster in functionally important splicing regions and can disrupt RNA splicing, but no well-established functional assay specific to p.Glu622Asp was identified.

Computational results are mixed: REVEL is 0.455, BayesDel is -0.0897007, and SpliceAI predicts a possible splice effect with a maximum delta score of 0.27, so in silico evidence does not clearly support either a damaging or benign interpretation.

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, and available PVS1 review indicates it does not fall within the generic null-variant categories for PVS1 application such as nonsense, frameshift, or canonical +/-1 or 2 splice variants. Although SF3B1 was flagged as eligible for generic PVS1 consideration at the gene level, this specific variant type does not support PVS1.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	Not assessed	No evidence was identified showing that this exact amino acid change, p.Glu622Asp (p.E622D), matches a previously established pathogenic variant caused by a different nucleotide change.
PS2	Not assessed	No confirmed de novo occurrence with parental confirmation was identified for this variant.
PS3	Not assessed	Published studies show that SF3B1 alterations can disrupt splicing and cell function, but no well-established functional study specific to p.Glu622Asp was identified. Available gene-level functional literature therefore does not support applying PS3 to this exact variant.	PMID:21909114 PMID:25428262 oncokb
PS4	Not assessed	This variant has variant-specific somatic cancer context, but no germline case-control or affected-individual enrichment data were identified to show that it is significantly more common in affected individuals than in controls.	oncokb clinvar
PM1	Not met	Published studies show that recurrent SF3B1 missense variants cluster in the HEAT-repeat region, but the available hotspot review did not identify p.Glu622Asp or codon 622 as a statistically significant hotspot. Nearby regional clustering alone is not sufficient to apply PM1 for this variant.	hotspots PMID:21909114 PMID:25428262
PM2	Met	This variant is absent from gnomAD v2.1 and is present at very low frequency in gnomAD v4.1 with AF 2.478382310298422e-06 (0.00025%, 4/1613956 alleles), which is below the default PM2 threshold of 0.1%. This rarity supports PM2.	gnomad_v2 gnomad_v4
PM3	Not assessed	No evidence was identified showing this variant in trans with a pathogenic variant in a recessive disorder.
PM4	N/A	This is a missense substitution and does not cause a protein length change from an in-frame insertion, in-frame deletion, or stop-loss event.
PM5	Not assessed	No evidence was identified showing a different pathogenic missense change at codon 622 that would support PM5 for this novel amino acid substitution.
PM6	Not assessed	No assumed de novo occurrence without full parental confirmation was identified for this variant.
PP1	Not assessed	No segregation data were identified for this variant.
PP2	Not assessed	SF3B1 is known to harbor disease-relevant missense variation, but no gene-specific missense constraint rule or calibrated framework was identified here to support PP2 for this variant.
PP3	Not met	Available computational evidence is mixed rather than consistently damaging. REVEL is 0.455, BayesDel is -0.0897007, and SpliceAI shows a possible splice effect with max delta score 0.27, so the in silico evidence does not provide a clear basis to apply PP3.	revel bayesdel spliceai
PP4	Not assessed	No phenotype information was provided that is sufficiently specific for a single-gene or narrow differential diagnosis assessment.
PP5	N/A	Assertion-based pathogenic evidence was not used for this review, and no qualifying external classification source was identified for this variant.	clinvar
BA1	Not met	The observed gnomAD v4.1 allele frequency is 2.478382310298422e-06 (0.00025%), which is well below the default BA1 threshold of 1%, so BA1 is not met.	gnomad_v4
BS1	Not met	The observed gnomAD v4.1 allele frequency is 2.478382310298422e-06 (0.00025%), which is below the default BS1 threshold of 0.3%, so BS1 is not met.	gnomad_v4
BS2	Not assessed	This variant is rare in population databases and no evidence was identified showing observation in healthy adults in a manner sufficient to apply BS2.	gnomad_v4
BS3	Not assessed	No well-established functional study showing no damaging effect for p.Glu622Asp was identified.	PMID:21909114 PMID:25428262 oncokb
BS4	Not assessed	No non-segregation evidence was identified for this variant.
BP1	N/A	This is a missense variant in a gene where disease-relevant missense variation is established, so BP1 does not apply.	PMID:21909114 PMID:25428262
BP2	Not assessed	No phase data were identified to show this variant occurs in cis with a pathogenic variant or in trans in a manner supporting BP2.
BP3	Not assessed	No evidence was identified showing that this missense change is located in a repetitive region without known function that would support BP3.
BP4	Not met	Available computational evidence does not provide a clearly benign prediction. REVEL is 0.455, BayesDel is -0.0897007, and SpliceAI predicts a possible splice effect with max delta score 0.27, so BP4 is not supported.	revel bayesdel spliceai
BP5	Not assessed	No evidence was identified for an alternate molecular explanation for disease that would support BP5.
BP6	N/A	Assertion-based benign evidence was not used for this review, and no qualifying external benign classification source was identified for this variant.	clinvar
BP7	N/A	This criterion is for synonymous or certain noncoding variants with no predicted splice impact, and it does not apply to this missense variant.

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.