No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.
Likely benign.A likely benign classification under the recorded framework.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.SMAD4 encodes a protein that helps transmit TGF-beta and bone morphogenetic protein signals to the nucleus, where it controls genes involved in cell growth and tissue development. It acts as a tumor suppressor and is associated with juvenile polyposis syndrome and hereditary hemorrhagic telangiectasia. Loss or alteration of SMAD4 is especially linked to pancreatic cancer and can also occur in colorectal and lung cancers.
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
No pathogenic criterion marked as applied in the recorded assessment.
Met: gnomAD v4.1 frequency of 0.525% in African/African American individuals exceeds the 0.3% BS1 disease-frequency ceiling.
Met: SpliceAI maximum delta 0.008 is below the <0.1 BP4 threshold, predicting no significant splice impact.
No SMAD4-specific framework was available, so generic ACMG/AMP 2015 combination rules applied: supporting BS1 and BP4 yield Likely Benign.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 477 / 1,574,666 alleles. Recorded AF 0.000302921. Recorded homozygote count 1.
This variant is present in gnomAD v2.1 (AF= 0.000510649; MAF= 0.05106%, 144/281994 alleles, homozygotes = 1) and has highest observed frequency in the African/African American population (AF= 0.00481928; MAF= 0.48193%, 120/24900 alleles, homozygotes = 0); grpmax FAF= 0.00406717.
Not available in gnomAD-Canada v1.0.
Recorded SpliceAI maximum delta score: 0.008. Refer to the recorded PP3/BP4 rationale for interpretation.
1 Likely benign.
No standalone functional evidence summary is recorded in evidence_summary.functional.
This variant has previously been reported in somatic cancers (COSMIC; COSV61686743, n = 1 times).
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 8 not met · 12 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
No ClinGen/SMAD4-specific VCEP framework was available in the bundle, so generic ACMG/AMP definitions were used.
The evidence bundle contains population, ClinVar, splice-prediction, and somatic-cancer observations, but no proband, parental-testing, pedigree, meiosis, segregation, or non-segregation evidence relevant to PS2, PM6, PP1, or BS4.
All four requested criteria are therefore not_assessed rather than inferred from another source's classification.
The variant is non-missense and non-canonical intronic; only the calibrated SpliceAI path was used for PP3/BP4.
BP4 is met at supporting strength from SpliceAI maximum delta 0.008, below the generic <0.1 threshold. PP3 and BP7 are not applied.
No ClinGen CSPEC/VCEP or gene-specific framework was available, so generic ACMG/AMP population rules were used.
The variant shows a strong ancestry-specific frequency signal: BS1 is met, whereas BA1 is not met because the maximum frequency is below 1%.
The single observed homozygote is flagged for human review rather than used automatically for BS2 because unaffected adult status and genotype validity are not documented.
PM2 is not met because the variant is present at a frequency above the case's extreme-rarity threshold in the highest-frequency ancestry group.
No criteria match.
BS1 is met because the variant's maximum ancestry-specific frequency exceeds the generic disease-frequency ceiling used for this case. gnomAD v4.1 reports AF 0.52515% in African/African American individuals and grpmax FAF 0.48210%; gnomAD v2.1 reports AF 0.48193% and grpmax FAF 0.40672%. These values exceed the case's generic BS1 threshold of 0.3%.
Generic ACMG/AMP BS1: allele frequency is greater than expected for the disorder; in this case the generic threshold is >0.3% in a relevant ancestry group.
Met at supporting strength. This +23 intronic variant is assessed only on the splice-impact path. No SMAD4 VCEP/CSPEC or local gene-specific computational rule was available. SpliceAI maximum delta is 0.008 (reported as 0.01), below the generic BP4 threshold of <0.1, predicting no significant splice impact.
Generic non-missense splice-impact calibration: SpliceAI maximum delta <0.1 supports BP4; 0.008 meets this threshold.
Generic ACMG/AMP fallback applies because no SMAD4 VCEP/gene-specific specification was retrieved. Although SMAD4 loss of function is an established germline disease mechanism, NM_005359.6:c.454+23C>T is a deep intronic, non-canonical splice-position substitution (intron 4), not a nonsense, frameshift, or canonical ±1/2 splice variant. No altered transcript or protein consequence is established, and SpliceAI shows no predicted significant splice effect (maximum delta 0.008). Therefore, this variant is not established as a null allele and PVS1 is not met.
Generic PVS1 (ClinGen SVI PVS1 framework): apply only when a variant is predicted to cause loss of function in a gene for which loss of function is an established disease mechanism; this non-canonical deep intronic substitution has no demonstrated splice or null consequence.
PM2 is not met because the variant is clearly present in population databases and its maximum ancestry-specific frequency is not extremely rare. gnomAD v4.1 reports AF 0.52515% in African/African American individuals (grpmax FAF 0.48210%), and gnomAD v2.1 reports AF 0.48193% in that population (grpmax FAF 0.40672%). These frequencies exceed the case's generic PM2 rarity threshold of <0.1% when ancestry-specific frequencies are considered.
Generic ACMG/AMP PM2: the variant is absent or extremely rare in population databases; in this case the generic rarity threshold is <0.1% after considering relevant ancestry groups.
NM_005359.6:c.454+23C>T is an intronic single-nucleotide substitution with predicted protein consequence p.?. It is not an in-frame insertion/deletion, stop-loss, or other demonstrated protein-length-changing variant. No altered transcript or protein product has been shown. PM4 is not met.
Generic ACMG/AMP PM4: protein length changes caused by in-frame deletions/insertions in a non-repeat region or stop-loss variants; no qualifying protein-length change is demonstrated.
Not met. This is a +23 intronic, non-canonical-splice-position variant, so the splice-impact path is applicable. No SMAD4 VCEP/CSPEC or local gene-specific computational rule was available; under the generic SpliceAI rule, the observed maximum delta (0.008; reported as 0.01) is below the PP3 threshold of >0.2.
Generic non-missense splice-impact calibration: SpliceAI maximum delta >0.2 supports PP3; 0.008 is below this threshold.
The exact ClinVar record has Likely benign single-submitter laboratory assertions and no expert-panel submission; therefore it cannot support PP5.
Apply PP5 only to an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic assertion.
BA1 is not met. The maximum observed population frequency is 0.52515% in gnomAD v4.1 African/African American individuals (grpmax FAF 0.48210%), below the generic BA1 threshold of 1%.
Generic ACMG/AMP BA1: allele frequency is greater than 5% in a population database; this assessment uses the case framework's generic population threshold of 1%.
BP3 concerns an in-frame deletion/insertion in a repetitive region without known function. This variant is a single-nucleotide intronic substitution, not an in-frame deletion or insertion; repeat-region context therefore cannot make it eligible for BP3. BP3 is not met.
Generic ACMG/AMP BP3: an in-frame deletion/insertion in a repetitive region without a known function; the variant is not an in-frame deletion/insertion.
Although the exact ClinVar record is labeled Likely benign, it has only single-submitter laboratory assertions and no expert-panel submission; it cannot support BP6.
Apply BP6 only to an exact-variant ClinVar expert-panel Benign or Likely benign assertion.
No proband-specific de novo observation is documented in the case-evidence bundle. There is no documented parental testing, parental genotype, or confirmation that the variant is absent in both biological parents; therefore PS2 cannot be assessed.
Generic ACMG/AMP PS2 requires confirmed de novo occurrence in the patient with confirmed maternity and paternity; no applicable SMAD4-specific specification was available.
No validated functional assay evidence for SMAD4 NM_005359.6:c.454+23C>T is present in the case bundle. The variant is a deep intronic change (c.454+23) with no reported RNA/cDNA, minigene, protein, or other disease-relevant assay result. The available SpliceAI prediction is computational and is not sufficient for PS3.
No case-control study, affected-case count, control count, or statistically assessed enrichment for NM_005359.6(SMAD4):c.454+23C>T was retrieved.
Generic ACMG/AMP PS4: increased prevalence in affected individuals compared with controls requires variant-specific enrichment evidence.
No affected-proband observations, phase data, or co-occurring pathogenic/likely pathogenic variant in trans were provided for NM_005359.6:c.454+23C>T. Therefore PM3 cannot be assessed. The available records contain population, ClinVar, splice-prediction, and somatic-cancer information, none of which establishes PM3 evidence.
Generic ACMG/AMP PM3: consider pathogenicity when the variant is observed in trans with a pathogenic variant in an affected individual, with strength determined by the applicable inheritance model and quality of phase/case evidence.
No likely de novo occurrence is documented. The bundle provides no parental testing, family history, maternity or paternity confirmation, or case report describing this variant in an apparently de novo proband; therefore PM6 cannot be assessed.
Generic ACMG/AMP PM6 concerns a likely de novo occurrence without confirmed maternity and paternity; no applicable SMAD4-specific specification was available.
No affected or unaffected relatives, informative meioses, family pedigree, phenotype segregation, or genotype results in relatives are documented. The variant cannot be evaluated for cosegregation with disease; therefore PP1 cannot be assessed.
Generic ACMG/AMP PP1 requires cosegregation of the variant with disease in affected family members, with strength dependent on the amount and informativeness of segregation; no applicable SMAD4-specific specification was available.
No proband phenotype, clinical diagnosis, or phenotype-to-SMAD4 specificity assessment was supplied for this variant.
Generic ACMG/AMP PP4: the patient's phenotype or family history must be highly specific for a disease with a single genetic etiology.
A single homozygote is reported in gnomAD v2.1 and a single homozygote is reported in gnomAD v4.1, both in the Admixed American population. This is potentially relevant to BS2 for an autosomal-dominant SMAD4 disorder, but the bundle does not establish that the individual was a healthy adult, clinically evaluated for SMAD4-associated disease, or free of reduced penetrance disease. The observation may also represent a population-database or genotype-quality artifact, so BS2 is not assigned automatically.
Generic ACMG/AMP BS2: the variant is observed in a healthy adult in a recessive disorder or in a homozygous state for a dominant disorder; phenotype and technical validity must be adequate.
No validated functional assay demonstrating a normal effect of SMAD4 NM_005359.6:c.454+23C>T is present in the case bundle. The low SpliceAI score is not an experimental result and cannot establish BS3. The single-submitter ClinVar likely benign classification is not functional evidence and is not used to infer this criterion.
No unaffected relatives who were adequately phenotyped and tested for the exact variant are documented. Consequently, there is no reliable non-segregation evidence to evaluate BS4.
Generic ACMG/AMP BS4 requires lack of segregation in affected family members or presence of the variant in unaffected family members when the phenotype is expected to be present and adequately assessed; no applicable SMAD4-specific specification was available.
No co-occurring pathogenic or likely pathogenic variant with documented cis or trans phase was provided for NM_005359.6:c.454+23C>T. Consequently, the benign allelic observation criterion BP2 cannot be assessed. Population observations and the single-submitter ClinVar likely-benign classification do not constitute BP2 evidence.
Generic ACMG/AMP BP2: consider benignity when the variant is observed with a pathogenic variant in trans for a fully penetrant dominant disorder or in cis with a pathogenic variant, provided the phase and relevant inheritance context are established.
No affected individual, phenotype, or evidence of an alternative molecular diagnosis was supplied.
Generic ACMG/AMP BP5: a variant may be considered when it is found in a case with an alternate molecular basis for disease.
PS1 evaluates a missense variant that produces the same amino-acid change as an established pathogenic variant. The assessed variant is NM_005359.6:c.454+23C>T, an intronic variant in exon 4i with an unknown protein consequence (NP_005350.1:p.?), so no amino-acid change or codon-level comparison can be made.
PM1 evaluates a missense variant located in a mutational hot spot or critical and well-established functional domain without benign variation. The assessed variant is intronic (c.454+23C>T) with no amino-acid residue assigned, and vcep_materials.json contains no SMAD4 domain table. A protein-residue or missense-domain assessment is therefore not applicable.
PM5 evaluates novel missense changes at an amino-acid residue where a different missense change is established as pathogenic. The assessed variant is intronic, has no assigned amino-acid residue, and cannot be compared with same-residue missense variants; the case PM5 artifact also reports no safely confirmable same-residue candidates.
PP2 is a gene-level missense criterion intended for genes in which missense variation is a common disease mechanism and benign missense variation is uncommon. The assessed variant is intronic rather than missense, and the case evidence provides no protein consequence; PP2 therefore cannot be applied to this variant.
BP1 is a gene-level benign criterion for a missense variant in a gene where truncating variants are a known disease mechanism and missense variants are not. The assessed variant is intronic, not missense, and has no assigned protein consequence; BP1 is therefore not applicable.
Not applicable. BP7 is restricted to synonymous variants; NM_005359.6:c.454+23C>T is an intronic variant.
BP7 applies only to synonymous variants.
Every interpreted variant in SMAD4, mapped onto the exon structure of NM_005359.6. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| African/African American390 / 74,264 | 0.0053 |
| Middle Eastern7 / 5,870 | 0.0012 |
| Admixed American29 / 59,610 | 0.000491 hom |
| Remaining individuals28 / 61,098 | 0.00046 |
| European (non-Finnish)23 / 1,145,296 | 2e-05 |
| African/African American120 / 24,900 | 0.0048 |
| Admixed American20 / 35,326 | 0.000571 hom |
| Remaining individuals1 / 7,202 | 0.00014 |
| European (non-Finnish)3 / 128,690 | 2.3e-05 |
This variant is present in gnomAD v4.1 (AF= 0.000302921; MAF= 0.03029%, 477/1574666 alleles, homozygotes = 1) and has highest observed frequency in the African/African American population (AF= 0.00525154; MAF= 0.52515%, 390/74264 alleles, homozygotes = 0); grpmax FAF= 0.004821.
This variant is present in gnomAD v2.1 (AF= 0.000510649; MAF= 0.05106%, 144/281994 alleles, homozygotes = 1) and has highest observed frequency in the African/African American population (AF= 0.00481928; MAF= 0.48193%, 120/24900 alleles, homozygotes = 0); grpmax FAF= 0.00406717.
Not available in gnomAD-Canada v1.0.
Met at supporting strength. This +23 intronic variant is assessed only on the splice-impact path. No SMAD4 VCEP/CSPEC or local gene-specific computational rule was available. SpliceAI maximum delta is 0.008 (reported as 0.01), below the generic BP4 threshold of <0.1, predicting no significant splice impact.
Generic non-missense splice-impact calibration: SpliceAI maximum delta <0.1 supports BP4; 0.008 meets this threshold.
Not met. This is a +23 intronic, non-canonical-splice-position variant, so the splice-impact path is applicable. No SMAD4 VCEP/CSPEC or local gene-specific computational rule was available; under the generic SpliceAI rule, the observed maximum delta (0.008; reported as 0.01) is below the PP3 threshold of >0.2.
Generic non-missense splice-impact calibration: SpliceAI maximum delta >0.2 supports PP3; 0.008 is below this threshold.
Not applicable. BP7 is restricted to synonymous variants; NM_005359.6:c.454+23C>T is an intronic variant.
BP7 applies only to synonymous variants.
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
1 paper record listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Assays that assess the impact of variants at the mRNA level can be highly informative when evaluating the effects of variants at splice junctions and within coding sequences, untranslated regions, as well as deeper intronic regions (e.g. mRNA stability, processing or translation). Technical approaches include direct analysis of RNA and/or cDNA derivatives and in vitro minigene splicing assays.
Proposed Criteria for Interpretation of Sequence Variants, PS3 BS3 Functional studies
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
This variant is present in gnomAD v4.1 (AF= 0.000302921; MAF= 0.03029%, 477/1574666 alleles, homozygotes = 1) and has highest observed frequency in the African/African American population (AF= 0.00525154; MAF= 0.52515%, 390/74264 alleles, homozygotes = 0); grpmax FAF= 0.004821.
This variant is present in gnomAD v2.1 (AF= 0.000510649; MAF= 0.05106%, 144/281994 alleles, homozygotes = 1) and has highest observed frequency in the African/African American population (AF= 0.00481928; MAF= 0.48193%, 120/24900 alleles, homozygotes = 0); grpmax FAF= 0.00406717.
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Likely benign (1 clinical laboratory). (ClinVarID = 1802934)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
This variant has previously been reported in somatic cancers (COSMIC; COSV61686743, n = 1 times).