NM_005359.6:c.463A>G

SMAD4 · NP_005350.1:p.(Ser155Gly) · NM_005359.6

GRCh37: chr18:48581159 A>G · GRCh38: chr18:51054789 A>G

Gene: SMAD4 Transcript: NM_005359.6

Final call

VUS

PM2 supporting

Variant details

Gene

SMAD4

Transcript

NM_005359.6

Protein

NP_005350.1:p.(Ser155Gly)

gnomAD AF

1.8819679864699047e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

VUS: PM2 (supporting) is met because the gnomAD v4.1 maximum observed subpopulation allele frequency is 2.23e-05, below 0.0001.

Final determination: Under the generic ACMG/AMP 2015 fallback, one supporting criterion alone does not meet any pathogenic, likely pathogenic, likely benign, or benign combination threshold, so the final call 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	PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_005359.6:c.463A>G in SMAD4 is a missense substitution predicted to produce NP_005350.1:p.(Ser155Gly). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not met	Not met: no established pathogenic variant shares this p.Ser155Gly change, and c.463A>G is the only nucleotide change at codon 155 that can encode glycine.	clinvar PMID:25741868
PS2	Not assessed	Not assessed: no documented proband-parent testing or confirmed de novo result is available for NM_005359.6:c.463A>G.
PS3	Not met	Not met: no functional study tested c.463A>G, and the 12-variant SMAD4 reporter assay panel (PMID:40835297) excludes it.	oncokb clinvar pvs1_gene_context PMID:25741868
PS4	Not assessed	Not assessed: no exact-variant case-control enrichment, affected-case count, odds ratio, or statistically supported excess was available.	clinvar PMID:28655553
PM1	Not met	Not met: residue 155 is not a statistically significant mutational hotspot and no approved SMAD4 critical-domain table or pathogenic codon-155 variant places it in a functional domain.	PMID:25741868 clinvar
PM2	Met	Met at supporting strength: gnomAD v4.1 all-comers allele frequency 1.88e-06 (3/1,594,076) and popmax 2.23e-05 are both below the 0.0001 PM2 threshold.	gnomad_v2 gnomad_v4 clinvar PMID:25741868
PM3	N/A	Not applicable: SMAD4-associated hereditary hemorrhagic telangiectasia and juvenile polyposis are listed with autosomal-dominant inheritance, so recessive biallelic evidence is not required.	PMID:28655553
PM4	N/A	PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_005359.6:c.463A>G in SMAD4 is a missense substitution predicted to produce NP_005350.1:p.(Ser155Gly). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not met	Not met: the three alternative codon-155 missense variants (p.Ser155Asn, p.Ser155Thr, p.Ser155Arg) are all classified Uncertain significance, so no pathogenic same-residue comparator exists.	clinvar pm5_candidates
PM6	Not assessed	Not assessed: no affected proband with presumed de novo inheritance and unavailable or untested parents is documented for this variant.
PP1	Not assessed	Not assessed: no affected relatives, informative meioses, or family cosegregation data are documented for NM_005359.6:c.463A>G.
PP2	Not met	Not met: although SMAD4 is missense-constrained (gnomAD mis_z 6.18), only 29 of 371 pathogenic/likely pathogenic ClinVar records (8%) are missense, so missense is not a common mechanism.	gnomad_v4 clinvar pvs1_gene_context
PP3	Not met	Not met: missense REVEL 0.484 is below the ClinGen SVI PP3 supporting threshold of >=0.644.	revel generic_acmg_combination_rules
PP4	Not assessed	Not assessed: no individual-level phenotype sufficiently specific for a SMAD4-associated disorder was provided for this variant carrier.
PP5	Not met	Not met: the exact ClinVar record has zero expert-panel submissions and no Pathogenic or Likely pathogenic expert-panel classification.	clinvar
BA1	Not met	Not met: the highest gnomAD subpopulation allele frequency, 2.23e-05, is about three orders of magnitude below the 0.05 BA1 stand-alone threshold.	gnomad_v2 gnomad_v4 PMID:25741868
BS1	Not met	Not met: the highest observed allele frequency, 2.23e-05, is more than two orders of magnitude below the 0.01 BS1 threshold (Whiffin 2017).	gnomad_v2 gnomad_v4 PMID:25741868
BS2	Not met	Not met: zero homozygotes for c.463A>G in any gnomAD dataset (v2.1 and v4.1), and SMAD4 disease is not fully penetrant at an early age.	gnomad_v2 gnomad_v4 PMID:25741868
BS3	Not met	Not met: no functional assay tested c.463A>G, so preserved BMP/TGF-beta signalling for p.(Ser155Gly) is unproven, not demonstrated.	oncokb clinvar pvs1_gene_context PMID:25741868
BS4	Not assessed	Not assessed: no informative unaffected relatives with documented negative testing and adequate phenotype assessment are available for BS4.
BP1	Not met	Not met: 29 of 371 pathogenic/likely pathogenic SMAD4 ClinVar records are missense, so SMAD4 disease is not caused by truncating variants alone and BP1 does not apply.	clinvar pvs1_gene_context
BP2	Not assessed	Not assessed: no documented phase, cis/trans relationship, or second pathogenic variant is available for this SMAD4 c.463A>G observation.	clinvar PMID:28655553
BP3	N/A	BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_005359.6:c.463A>G in SMAD4 is a missense substitution predicted to produce NP_005350.1:p.(Ser155Gly). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: missense REVEL 0.484 exceeds the ClinGen SVI BP4 supporting threshold of <=0.29.	revel generic_acmg_combination_rules
BP5	Not assessed	Not assessed: no exact-variant affected case with a documented alternate molecular basis for disease was identified.	clinvar PMID:28655553
BP6	Not met	Not met: the exact ClinVar Likely benign assertion is from a single laboratory, with zero expert-panel submissions.	clinvar
BP7	N/A	BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_005359.6:c.463A>G in SMAD4 is a missense substitution predicted to produce NP_005350.1:p.(Ser155Gly). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules

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