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

Likely Benign

BS1 supporting 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

BS1 (Supporting): gnomAD v4.1 frequency of 0.525% in African/African American individuals exceeds the 0.3% benign frequency threshold.

2

BP4 (Supporting): SpliceAI maximum delta 0.008 is below the 0.1 threshold, predicting no significant splice impact.

3

BS1 plus BP4 (two supporting benign criteria) yields Likely Benign under generic ACMG/AMP 2015 combination rules.

Final determination: Under the generic ACMG/AMP 2015 fallback, two supporting benign criteria support a Likely Benign classification.

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	Not met	Not met: c.454+23C>T is deep intronic with a SpliceAI delta of 0.008, not a canonical splice or null variant.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework spliceai
PS1	N/A	Not applicable: this intronic variant has no amino-acid change, so it cannot match an established pathogenic missense substitution.
PS2	Not assessed	Not assessed: no parental testing was available to confirm the variant arose de novo in this individual.
PS3	Not assessed	Not assessed: no RNA, minigene, or protein assay was performed, and a SpliceAI prediction of 0.008 is computational only.
PS4	Not assessed	Not assessed: no case-control or affected-count data were available to test for enrichment in disease.
PM1	N/A	Not applicable: this intronic variant has no amino-acid residue, so hotspot or functional-domain assessment cannot be applied.
PM2	Not met	Not met: gnomAD v4.1 frequency reaches 0.525% in African/African American individuals, above the <0.1% PM2 rarity threshold.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no phase data or co-occurring pathogenic variant in trans were available to evaluate this recessive criterion.
PM4	Not met	Not met: this single-nucleotide intronic substitution does not change protein length, unlike in-frame indels or stop-loss variants.	pvs1_variant_assessment spliceai
PM5	N/A	Not applicable: this intronic variant has no assigned amino-acid residue, so no same-residue pathogenic missense comparison is possible.
PM6	Not assessed	Not assessed: no parental testing or family data were available to support a de novo occurrence.
PP1	Not assessed	Not assessed: no family pedigree or relative genotype data were available to evaluate cosegregation with disease.
PP2	N/A	Not applicable: PP2 targets missense variants in missense-driven genes, but this variant is intronic with no protein consequence.
PP3	Not met	Not met: SpliceAI maximum delta 0.008 falls well below the >0.2 PP3 threshold for predicted splice impact.	spliceai
PP4	Not assessed	Not assessed: no proband phenotype or clinical diagnosis was supplied to assess phenotype specificity to SMAD4.
PP5	Not met	Not met: the ClinVar record is a single-submitter Likely benign assertion with no expert-panel review.	clinvar
BA1	Not met	Not met: maximum population frequency of 0.525% in gnomAD v4.1 African/African American individuals is below the 1% BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Met	Met: gnomAD v4.1 frequency of 0.525% in African/African American individuals exceeds the 0.3% BS1 disease-frequency ceiling.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: two homozygotes are reported, but healthy-adult status and clinical evaluation were not established.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no functional assay showing a normal splicing or protein effect was available; SpliceAI 0.008 is computational only.
BS4	Not assessed	Not assessed: no phenotyped unaffected relatives were tested for this variant, so non-segregation cannot be evaluated.
BP1	N/A	Not applicable: BP1 concerns missense variants in truncating-driven genes, but this variant is intronic with no protein change.
BP2	Not assessed	Not assessed: no pathogenic variant with documented cis or trans phase was available to evaluate a benign allelic observation.
BP3	Not met	Not met: this is an intronic single-nucleotide substitution, not an in-frame indel in a repetitive region.	pvs1_variant_assessment
BP4	Met	Met: SpliceAI maximum delta 0.008 is below the <0.1 BP4 threshold, predicting no significant splice impact.	spliceai
BP5	Not assessed	Not assessed: no affected individual or alternative molecular diagnosis was supplied.
BP6	Not met	Not met: the ClinVar record is a single-submitter Likely benign assertion with no expert-panel submission.	clinvar
BP7	N/A	Not applicable: BP7 applies only to synonymous variants, and this variant is intronic.

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