NM_012433.2:c.2359del

SF3B1 · NP_036565.2:p.(Ile787LeufsTer3) · NM_012433.2

GRCh37: chr2:198266476 AT>A · GRCh38: chr2:197401752 AT>A

Gene: SF3B1 Transcript: NM_012433.2

Final call

Likely Pathogenic

PVS1 very strong PM2 moderate

Variant details

Gene

SF3B1

Transcript

NM_012433.2

Protein

NP_036565.2:p.(Ile787LeufsTer3)

gnomAD AF

0.0 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

PVS1 (very_strong): NM_012433.2:c.2359del is a frameshift deletion predicted to cause premature termination (p.Ile787LeufsTer3) in SF3B1, a gene in which germline loss of function is an established disease mechanism for neurodevelopmental disorders (PMC6185798; PMID:41577671).

PM2 (moderate): This variant is absent from large population databases including gnomAD v2.1 and v4.1 (0/1,609,404 alleles), consistent with rarity in the general population.

Classification of Likely Pathogenic is assigned based on 1 very strong criterion (PVS1) and 1 moderate criterion (PM2) under the generic ACMG/AMP 2015 combination rules (PMID:25741868).

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Pathogenic classification based on the observed combination of pathogenic criteria.

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	Met	NM_012433.2:c.2359del is a frameshift deletion predicted to cause premature termination at codon 789 (p.Ile787LeufsTer3), with the premature termination codon located well upstream of the normal terminus (residue 1305) in a gene where loss of function is an established disease mechanism for germline neurodevelopmental disorders.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment
PS1	N/A	PS1 applies to nucleotide substitutions producing the same amino acid change as an established pathogenic variant; this variant is a frameshift deletion.
PS2	N/A	No de novo observations are available for this variant in ClinVar, literature, or any evidence source.
PS3	N/A	No well-established in vitro or in vivo functional studies were identified for this specific variant.
PS4	N/A	No case-control or statistical prevalence data are available for this variant.
PS5	N/A	No reputable source has reported this variant as pathogenic with evidence unavailable for independent evaluation; the variant is absent from ClinVar.
PM1	Not met	This variant does not lie in a statistically significant mutational hotspot and is not located in a critical functional domain identified as a hotspot for pathogenic variation.
PM2	Met	This variant is absent from large population databases including gnomAD v2.1 and v4.1 (0/1,609,404 alleles), supporting rarity in the general population.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	Skipped per instruction — trivially not applicable.
PM4	N/A	PM4 applies to in-frame deletions/insertions or stop-loss variants; this is a frameshift deletion, which is assessed under PVS1.
PM5	N/A	PM5 applies to novel missense variants at residues with established pathogenic missense changes; this is a frameshift variant.
PM6	N/A	No de novo observation data available for this variant.
PP1	N/A	No cosegregation data with disease in multiple affected family members is available.
PP2	N/A	PP2 applies to missense variants in genes with low rate of benign missense variation; this is a frameshift variant.
PP3	Not met	Multiple lines of computational evidence do not independently support a deleterious effect beyond what is already captured by PVS1. REVEL and BayesDel are unavailable for this deletion variant, and SpliceAI predicts no significant splice impact (max delta score 0.02).	spliceai
PP4	N/A	No patient phenotype or family history data are available to assess specificity for a disease with a single genetic etiology.
PP5	N/A	No reputable source has reported this variant as pathogenic; the variant is absent from ClinVar.
BA1	Not met	The allele frequency in population databases is 0.00%, which does not exceed the 1% threshold for BA1.	gnomad_v2 gnomad_v4
BS1	Not met	The allele frequency in population databases is 0.00%, which does not exceed the 0.3% threshold for BS1.	gnomad_v2 gnomad_v4
BS2	N/A	The variant is absent from population databases; no observation in healthy adult individuals is available to contradict pathogenicity.
BS3	N/A	No well-established in vitro or in vivo functional studies demonstrating no damaging effect are available for this variant.
BS4	N/A	No family segregation data are available to assess lack of segregation with disease.
BP1	N/A	BP1 applies to missense variants in genes where primarily truncating variants cause disease; this variant itself is truncating.
BP2	N/A	No data available regarding observation in trans with a pathogenic variant or in cis with a pathogenic variant.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions; this is a frameshift variant.
BP4	Not met	Multiple lines of computational evidence do not suggest no impact. SpliceAI predicts no significant splice alteration (max delta 0.02), but the frameshift itself is inherently damaging and no computational evidence supports a benign effect on the truncated protein product.	spliceai
BP5	N/A	No data available regarding an alternate molecular basis for disease in a case harboring this variant.
BP6	N/A	No reputable source has reported this variant as benign; the variant is absent from ClinVar.
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact; this is a frameshift deletion.

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.