Variant classification summary

NM_005359.6:c.454+23C>T

SMAD4 · NP_005350.1:p.? · NM_005359.6

GRCh37: chr18:48575717 C>T · GRCh38: chr18:51049347 C>T

Gene: SMAD4 Transcript: NM_005359.6

Final call

VUS

BP4 supporting

Variant details

Gene

SMAD4

Transcript

NM_005359.6

Protein

NP_005350.1:p.?

gnomAD AF

0.00030292138142310815 (v4.1)

ClinVar

Likely benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

VUS: BP4 (supporting) was met because SpliceAI maximum delta 0.008 is below the <=0.1 threshold for no significant predicted splice impact.

Final determination: Under generic ACMG/AMP 2015 fallback rules, one supporting benign criterion alone does not meet the Likely Benign threshold of two supporting benign criteria, so the result is VUS.

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	Not applicable: c.454+23C>T is a non-canonical intronic variant with SpliceAI max delta 0.008 and no demonstrated protein-truncating or splice-loss consequence.	pvs1_generic_framework spliceai PMID:25741868
PS1	N/A	Not applicable: this intronic variant has unknown protein consequence and is not an amino-acid substitution.
PS2	Not assessed	Not assessed: no documented parental testing or confirmed de novo occurrence is available for this variant.	PMID:25741868
PS3	Not assessed	Not assessed: no variant-specific validated functional assay or assay result is available for NM_005359.6:c.454+23C>T.	PMID:25741868
PS4	Not assessed	Not assessed: no case-control cohort, odds ratio, or exact-variant prevalence comparison is available to establish affected-individual enrichment.
PM1	N/A	Not applicable: the intronic variant has unknown protein consequence, so no amino-acid residue can be evaluated for a critical domain or hotspot.
PM2	Not met	Not met: gnomAD v4.1 overall AF 0.000302921 exceeds the generic PM2 threshold of 0.0001.	gnomad_v4 gnomad_v2 PMID:25741868
PM3	Not assessed	Not assessed: no affected-proband observation, second pathogenic variant, phase result, or inheritance information is documented for this intronic SMAD4 variant.
PM4	N/A	Not applicable: the intronic SNV has protein consequence p.? and produces no established in-frame insertion, deletion, or protein-length change.
PM5	N/A	Not applicable: the intronic variant has unknown protein consequence, so no amino-acid residue exists for PM5 same-residue comparison.
PM6	Not assessed	Not assessed: no affected proband with a presumed de novo variant is documented, even without parental confirmation.	PMID:25741868
PP1	Not assessed	Not assessed: zero informative affected-relative genotypes or meioses are documented for segregation analysis.	PMID:25741868
PP2	N/A	Not applicable: PP2 is a missense criterion, whereas this variant is intronic with unknown protein consequence.
PP3	Not met	Not met: SpliceAI maximum delta 0.008 is below the >=0.2 supporting PP3 threshold.	spliceai
PP4	Not assessed	Not assessed: no patient phenotype, clinical diagnosis, or disease-specific family history is available to establish a highly specific phenotype match.
PP5	Not met	Not met: the exact ClinVar record has zero expert-panel submissions and only single-submitter Likely benign assertions.	clinvar
BA1	Not met	Not met: the highest default all-comers gnomAD v4.1 population AF is 0.005251535, below the generic BA1 threshold of 0.05.	gnomad_v4 gnomad_v2 PMID:25741868
BS1	Not met	Not met: the highest default all-comers gnomAD v4.1 population AF is 0.005251535, below the generic BS1 threshold of 0.01.	gnomad_v4 gnomad_v2
BS2	Not assessed	Not assessed: one gnomAD homozygote is reported, but age, phenotype, and clinical health of that individual are unavailable.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no variant-specific validated functional assay or assay result is available to demonstrate preserved function for NM_005359.6:c.454+23C>T.	PMID:25741868
BS4	Not assessed	Not assessed: no affected-family testing or documented non-segregation observation is available for this variant.	PMID:25741868
BP1	N/A	Not applicable: BP1 concerns missense variants, but this submitted variant is intronic with unknown protein consequence.
BP2	Not assessed	Not assessed: no additional pathogenic variant or validated cis/trans phase result is documented for this intronic SMAD4 variant.
BP3	N/A	Not applicable: c.454+23C>T is an intronic SNV, not an in-frame deletion in a repetitive protein region.
BP4	Met	Met, supporting: SpliceAI maximum delta 0.008 is below the <=0.1 BP4 threshold.	spliceai
BP5	Not assessed	Not assessed: no affected-individual phenotype or confirmed alternate molecular diagnosis is documented for this exact variant.
BP6	Not met	Not met: the exact ClinVar record has zero expert-panel submissions and only single-submitter Likely benign assertions.	clinvar
BP7	N/A	Not applicable: c.454+23C>T is intronic, not a synonymous coding variant eligible for BP7.

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.