No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
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.
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.
No benign criterion marked as applied in the recorded assessment.
VUS: PM2 (supporting) is the only applied criterion and does not satisfy a generic ACMG/AMP pathogenic or benign combination rule.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 3 / 1,594,076 alleles. Recorded AF 1.88197e-06. Recorded homozygote count 0.
This variant is present in gnomAD v2.1 (AF= 3.9781e-06; MAF= 0.00040%, 1/251376 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.79786e-06; MAF= 0.00088%, 1/113664 alleles, homozygotes = 0).
Not available in gnomAD-Canada v1.0.
Recorded REVEL score: 0.484. Refer to the recorded PP3/BP4 rationale for interpretation.
3 Uncertain significance · 1 Uncertain Significance · 1 Likely benign.
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. SMAD4, a transcription factor in the TGFß pathway, is frequently mutated in pancreatic and colorectal cancers.
This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
28 criteria with recorded statuses: 1 met · 14 not met · 8 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
No applicable SMAD4-specific VCEP or gene-specific framework was available, so generic ACMG/AMP criteria were considered.
The available case and exact-variant literature records contain no proband-parent testing, presumed de novo evidence, family segregation, informative meioses, or non-segregation data; all four requested criteria are not assessed.
Neither PS3 nor BS3 is met: no functional or mechanistic assay has tested SMAD4 c.463A>G (p.Ser155Gly), and the only SMAD4 functional assay identified (12-variant BMP/TGF-beta reporter panel, PMID:40835297) excludes this variant, so the functional evidence group contributes no pathogenic or benign weight to the final classification.
No SMAD4-specific ClinGen CSPEC/VCEP framework was available, so generic ACMG/AMP definitions were used where applicable.
PP5 and BP6 were not triggered because the exact ClinVar record has zero expert-panel submissions; non-expert laboratory assertions were excluded by rule.
The variant NM_005359.6:c.463A>G (SMAD4, NP_005350.1:p.(Ser155Gly); hg38 chr18:51054789 A>G) is extremely rare in every population dataset examined: gnomAD v4.1 all-comers AF 1.88197e-06 (3/1,594,076 alleles), gnomAD v2.1 all-comers AF 3.9781e-06 (1/251,376 alleles), and gnomAD v2.1 exomes-only non-cancer subset AF 4.2223e-06 (1/236,838 alleles), with the highest observed subpopulation frequency 2.23105e-05 (East Asian, v4.1).
Because of that rarity, PM2 is met at supporting strength (all values including the popmax proxy are <= 0.0001), while BA1 (>= 0.05), BS1 (>= 0.01) and BS2 (healthy adult observation with full early-age penetrance) are all not met.
No ClinGen CSPEC/VCEP or local gene-specific framework governs SMAD4 for this case, so the generic ACMG/AMP 2015 thresholds were applied and the all-comers gnomAD entries were the default source; the available non-cancer subsets were checked as a sensitivity analysis and give the same result.
Zero homozygotes were reported in every dataset, so no homozygous/healthy-adult frequency argument could be made in either direction.
No criteria match.
PM2 (absent from controls / extremely low frequency in population databases; Richards et al. 2015, PMID:25741868) applies. Under the supplied calibration, PM2 is applied at supporting strength with a threshold of <= 0.0001. NM_005359.6:c.463A>G (SMAD4 p.(Ser155Gly)) is present at a total allele frequency of 1.88197e-06 in gnomAD v4.1 all-comers (3/1,594,076 alleles, 0 homozygotes) and 3.9781e-06 in gnomAD v2.1 all-comers (1/251,376 alleles, 0 homozygotes); the exomes-only non-cancer subset of v2.1 gives 4.2223e-06 (1/236,838 alleles, 0 homozygotes) and the variant is absent from gnomAD v3.1 non-cancer genomes. Because the scrape did not return a popmax filtering allele frequency (grpmax_faf = null for v2.1 and v4.1), the highest observed subpopulation frequency was used as a conservative proxy: 2.231e-05 (1/44,822, East Asian, gnomAD v4.1) and 9.742e-06 in the v2.1 non-cancer exomes (European non-Finnish, 1/102,648). Even that most conservative ancestry-specific figure is below 0.0001, so the variant satisfies PM2 in every dataset and in every ancestry, including the non-cancer/exome-only subsets that would be the preferred controls for a hereditary cancer / vascular malformation disorder. No CSPEC/VCEP or local gene framework exists for SMAD4 in this case, so the all-comers gnomAD totals are the default source and confirm the result. Supporting rather than moderate strength is used per the supplied SVI recommendation to downgrade PM2 to supporting when the <= 0.0001 frequency threshold is applied. A ClinVar submission for this variant (ClinVar variation 374977) likewise cites population-database rarity.
frequency_very_low: max_population_af <= 0.0001 (PM2 supporting)
No SMAD4-specific VCEP/CSPEC framework exists, so the generic ACMG/AMP definition of PS1 was applied. PS1 requires that the same amino-acid change, here NP_005350.1:p.(Ser155Gly), has already been established as pathogenic regardless of the nucleotide change used to produce it. Codon 155 is AGT (Ser); the only single-nucleotide substitution within that codon that encodes glycine is c.463A>G itself, so no alternative nucleotide change can generate p.Ser155Gly. Consistent with this, no established pathogenic variant carrying this amino-acid change exists: the ClinVar record for this exact variant (NM_005359.6(SMAD4):c.463A>G, VCV000374977) is uncertain/conflicting with no expert-panel submission and no pathogenic assertion, and no other p.Ser155Gly-encoding allele was recovered from ClinVar. PS1 is therefore not met.
PS3 (Richards et al. 2015, PMID:25741868) requires variant-specific functional evidence that the allele has a damaging effect on protein function or splicing. No functional assay has tested NM_005359.6:c.463A>G (NP_005350.1:p.(Ser155Gly)). The only SMAD4-specific functional assay identified is Despas et al. 2025 (J Med Genet 62(12):741-749, PMID:40835297), which generated 12 SMAD4 variants by site-directed mutagenesis and tested their capacity to activate BMP- and TGF-beta-dependent luciferase reporters in a SMAD4-non-expressing cell line; its variant table lists c.303G>T, c.380G>T, c.1051G>A, c.1052A>G, c.1052A>T, c.1074dup, c.1081C>T, c.1082G>C, c.1245_1248del, c.1333C>T, c.1571G>T and c.1611_1613del, and c.463A>G is not among them. That study therefore neither tested this variant nor performed a saturation/tiling characterization of a residue range that includes position 155, so it cannot support PS3 even at supporting strength. OncoKB returns 'Unknown Oncogenic Effect' with no variant-specific reviewed functional evidence, and the ClinVar record carries no functional assay submission. PS3 is not met at any strength; it is recorded as not_met rather than not_applicable because functional evidence is a legitimate, currently unsatisfied evidence type for this missense variant.
PS3 requires variant-specific functional evidence of a damaging effect on protein function or splicing; a study-based range may only substitute for the exact variant when that study itself systematically assayed the range spanning the variant position (generic ACMG/AMP 2015, PMID:25741868).
No SMAD4 VCEP/CSPEC specification or approved critical-functional-domain table was available (the domain-table collection contains no entry for this gene), so generic PM1 was applied. PM1 requires the variant to lie in a mutational hotspot or in a critical, well-established functional domain without benign variation. Residue 155 is not a statistically significant mutational hotspot: the Cancer Hotspots query for SMAD4 S155 returned no hotspot row, and the COSMIC search for c.463A>G found no somatic record. No residue-level source in the case materials assigns codon 155 to a critical SMAD4 functional domain, and residue 155 lies in the linker region between the MH1 and MH2 domains rather than in the MH2 domain where SMAD4 disease-causing missense variants cluster. Finally, the residue shows no pathogenic enrichment: every SMAD4 codon-155 variant on record (p.Ser155Gly, p.Ser155Asn, p.Ser155Thr, p.Ser155Arg) is Uncertain significance and the synonymous p.Ser155= is Likely benign. PM1 is therefore not met.
No SMAD4 VCEP/CSPEC framework exists, so generic PM5 was applied. PM5 requires a different missense change at the same amino-acid residue to have been established as pathogenic. The automated PM5 candidate collection returned no candidates because classic same-residue semantics could not be confirmed, so the residue was checked directly. Three alternative missense variants at codon 155 exist on record - NM_005359.6(SMAD4):c.464G>A (p.Ser155Asn), c.464G>C (p.Ser155Thr) and c.465T>A (p.Ser155Arg) - and all three are classified Uncertain significance; the synonymous codon-155 change c.465T>C (p.Ser155=) is Likely benign. No pathogenic or likely pathogenic missense change at residue 155 has been established, so the prerequisite comparator for PM5 does not exist and PM5 is not met.
No SMAD4 VCEP/CSPEC framework exists, so generic PP2 was applied. PP2 requires both a low rate of benign missense variation in the gene and that missense variants are a common mechanism of disease. The first component is satisfied: gnomAD gene-level constraint for SMAD4 is strongly missense-constrained (mis_z 6.18, oe_mis 0.45, pLI ~1.0), well beyond the conventional missense Z significance value. The second component fails. Among 371 SMAD4 ClinVar records classified Pathogenic, Likely pathogenic or Pathogenic/Likely pathogenic, 238 (64%) are truncating (frameshift/nonsense/stop-lost), 33 (9%) are splice-site variants and only 29 (8%) are missense, so missense variants are a minority mechanism rather than a common one. The case gene-context finding likewise supports a loss-of-function germline disease mechanism for SMAD4. Because the missense-as-common-mechanism requirement is not met, PP2 is not applied.
The variant is a missense substitution, NP_005350.1:p.(Ser155Gly), so the generic fallback requires the missense-specific REVEL path and does not substitute the splice-path SpliceAI result. REVEL is 0.484. This is below the supplied ClinGen SVI PP3 supporting threshold of >=0.644 (moderate >=0.773; strong >=0.932). BayesDel is not usable because no generic ACMG-strength calibration is established. Therefore PP3 is not met.
Generic ClinGen SVI missense calibration: REVEL >=0.644 for PP3 supporting, with higher thresholds for moderate and strong PP3.
PP5 is restricted here to an exact-variant ClinVar expert-panel classification of Pathogenic or Likely pathogenic. The exact ClinVar record has zero expert-panel submissions; its classifications are uncertain significance or likely benign from individual laboratories. These submissions cannot trigger PP5.
PP5 applies only when an exact-variant ClinVar expert panel classifies the variant as Pathogenic or Likely pathogenic; no applicable SMAD4-specific VCEP rule was available.
BA1 (stand-alone benign; Richards et al. 2015, PMID:25741868) requires an allele frequency of at least 0.05. NM_005359.6:c.463A>G (SMAD4, NP_005350.1:p.(Ser155Gly), hg38 chr18:51054789 A>G / hg37 18:48581159 A>G) is essentially absent from all population datasets examined. gnomAD v2.1 all-comers: total AF 3.978e-06 (1/251,376 alleles), exome-only, 0 homozygotes. gnomAD v4.1 all-comers: total AF 1.882e-06 (3/1,594,076 alleles), 0 homozygotes. The v2.1 exomes-only non-cancer subset gives AF 4.222e-06 (1/236,838 alleles). The highest frequency in any subpopulation is 2.231e-05 (1/44,822 alleles, East Asian, gnomAD v4.1); within the v2.1 non-cancer exomes the highest subpopulation frequency is 9.742e-06 (1/102,648, European non-Finnish). Every one of these values is roughly three orders of magnitude below 0.05, so the stand-alone benign frequency threshold is not approached in any ancestry, in either all-comers or non-cancer data. No ClinGen VCEP/CSPEC specification or local gene-specific framework exists for SMAD4 in this case (framework_mode = generic_acmg; final_classification_framework.found = false), so the generic ACMG/AMP 2015 frequency thresholds apply rather than any VCEP-specific non-cancer or exome-only source preference. The ACMG/AMP 2015 BA1 threshold of 0.05 was taken verbatim from the published calibration values supplied for this assessment and is attributable to Richards et al. 2015 (PMID:25741868).
frequency_stand_alone_benign: max_population_af >= 0.05
BS1 (strong benign; allele frequency greater than expected for the disorder) requires an allele frequency of at least 0.01 under the generic SVI default applied here, since no VCEP- or gene-derived threshold exists for SMAD4 in this case. NM_005359.6:c.463A>G (SMAD4 p.(Ser155Gly)) has a maximum observed allele frequency of 2.231e-05 (1/44,822 alleles, East Asian, gnomAD v4.1 all-comers) and 9.742e-06 in the highest subpopulation of the v2.1 exomes-only non-cancer subset (European non-Finnish, 1/102,648); the all-comers totals are 1.882e-06 (v4.1) and 3.978e-06 (v2.1), with 0 homozygotes throughout. All values are more than two orders of magnitude below 0.01, so the variant is far rarer than any plausible benign-frequency expectation, including for a relatively common dominant disorder such as hereditary haemorrhagic telangiectasia (population prevalence on the order of 1 in 5,000-10,000). The threshold used (0.01, generic SVI default; per-gene derivation preferred) is attributable to Whiffin et al. 2017 (PMID:28518168) as supplied in the published calibration values; a per-gene derivation was not possible here because no calibrated SMAD4-specific framework was available in this case.
frequency_strong_benign: max_population_af >= 0.01
BS2 requires the variant to be observed in a healthy adult individual with full penetrance expected at an early age (homozygous for a recessive, heterozygous for a dominant, or hemizygous for an X-linked disorder). Across every population dataset examined, NM_005359.6:c.463A>G (SMAD4 p.(Ser155Gly)) has zero homozygotes: gnomAD v2.1 all-comers (1/251,376 alleles, homozygotes = 0), gnomAD v2.1 exomes-only non-cancer subset (1/236,838, homozygotes = 0), gnomAD v4.1 all-comers (3/1,594,076, homozygotes = 0), and the variant is absent from gnomAD v3.1 non-cancer genomes. There is therefore no homozygous or biallelic observation that could constitute BS2 evidence. This is consistent with SMAD4-related disease being an autosomal dominant, incompletely and age-dependently penetrant condition (juvenile polyposis syndrome / hereditary haemorrhagic telangiectasia), for which BS2 is not an appropriate criterion even if adult heterozygous carriers exist in the population, because full early-age penetrance is not expected.
observed_homozygote_or_fully_penetrant_healthy_adult
BS3 (Richards et al. 2015, PMID:25741868) requires functional evidence - or a validated functional assay with established controls - showing that the variant has no damaging effect on protein function or splicing. No functional assay has tested NM_005359.6:c.463A>G (NP_005350.1:p.(Ser155Gly)). The SMAD4 reporter assay by Despas et al. 2025 (PMID:40835297) is the only SMAD4 functional assay identified, and its 12-variant panel (c.303G>T, c.380G>T, c.1051G>A, c.1052A>G, c.1052A>T, c.1074dup, c.1081C>T, c.1082G>C, c.1245_1248del, c.1333C>T, c.1571G>T, c.1611_1613del) does not include c.463A>G. OncoKB reports 'Unknown Oncogenic Effect' with no variant-specific functional data, and COSMIC and Cancer Hotspots contain no record of this variant. The absence of an assay is not evidence of preserved function, and no reviewed source demonstrates normal BMP/TGF-beta signalling for p.(Ser155Gly). BS3 is therefore not met at any strength, including supporting.
BS3 requires functional evidence (validated assay, with controls) showing no damaging effect of the variant on protein function or splicing (generic ACMG/AMP 2015, PMID:25741868).
No SMAD4 VCEP/CSPEC framework exists, so generic BP1 was applied. BP1 requires a gene in which primarily truncating variants are known to cause disease, i.e. a gene where missense variation is not an established pathogenic mechanism. SMAD4 pathogenicity is indeed truncated-variant-predominant - 238 of 371 (64%) Pathogenic/Likely pathogenic ClinVar records are frameshift/nonsense/stop-lost and a further 33 (9%) are splice-site variants - but pathogenic missense variants are nonetheless an established cause of SMAD4-associated disease: 29 Pathogenic/Likely pathogenic ClinVar records are missense, they cluster in the SMAD4 MH2 domain, and a dedicated cell-based functional assay has been developed specifically to classify SMAD4 missense variants from an HHT cohort (Despas et al., J Med Genet 2025, PMID:40835297). Because missense variants are a recognised disease mechanism for this gene, it is not a gene for which primarily truncating variants alone cause disease, and BP1 is not applied. Note also that this variant lies in the linker region rather than in the missense-rich MH2 domain.
The variant is a missense substitution, NP_005350.1:p.(Ser155Gly), so the generic fallback requires the missense-specific REVEL path and does not substitute the splice-path SpliceAI result. REVEL is 0.484. This is above the supplied ClinGen SVI BP4 supporting threshold of <=0.29 (moderate <=0.183; strong <=0.016). BayesDel is not usable because no generic ACMG-strength calibration is established. Therefore BP4 is not met.
Generic ClinGen SVI missense calibration: REVEL <=0.29 for BP4 supporting, with lower thresholds for moderate and strong BP4.
BP6 is restricted here to an exact-variant ClinVar expert-panel classification of Benign or Likely benign. The exact ClinVar record has zero expert-panel submissions; its Likely benign classification is from a single clinical laboratory. That non-expert assertion cannot trigger BP6.
BP6 applies only when an exact-variant ClinVar expert panel classifies the variant as Benign or Likely benign; no applicable SMAD4-specific VCEP rule was available.
No confirmed de novo observation is documented for NM_005359.6:c.463A>G (NP_005350.1:p.(Ser155Gly)). The available evidence does not identify the proband, parental genotypes, validated maternity and paternity, or testing of both parents; therefore PS2 cannot be applied.
No qualifying case-control enrichment analysis, affected-case count, odds ratio, or statistically supported excess of this exact variant was identified. The exact-variant ClinVar record contains only non-expert laboratory submissions, and the reviewed paper extract for PMID:28655553 explicitly states that NM_005359.6:c.463A>G/p.(S155G) was not reported. Generic PS4 requires significantly increased prevalence in affected individuals compared with controls; the available evidence is insufficient to assess that requirement.
Generic PS4: significantly increased prevalence of the exact variant in affected individuals compared with appropriate controls; no applicable SMAD4-specific VCEP rule was available.
No presumed de novo occurrence is documented for NM_005359.6:c.463A>G. There is no report of an affected proband with unavailable or untested parents, no parental phenotype information, and no case-level evidence sufficient to distinguish PM6 from an untested inherited variant.
No affected relatives carrying NM_005359.6:c.463A>G are documented, and no family pedigree, number of informative meioses, genotype-phenotype correlation, or cosegregation data are available. PP1 therefore cannot be applied at any strength.
No patient phenotype, clinical presentation, or highly specific disease-feature description for the individual carrying NM_005359.6:c.463A>G was provided in the available evidence. Gene-level associations of SMAD4 with hereditary hemorrhagic telangiectasia and juvenile polyposis do not establish a specific phenotype for this variant carrier. Therefore, the highly specific phenotype requirement for PP4 cannot be assessed.
Generic PP4: the patient's phenotype or family history is highly specific for a disease with a single-gene etiology; no applicable SMAD4-specific VCEP rule was available.
No unaffected relatives who are informative for inheritance are documented as lacking NM_005359.6:c.463A>G. The available records contain no pedigree, genotype results in unaffected relatives, age-related phenotype assessment, or non-segregation analysis; BS4 cannot be applied.
No SMAD4-specific VCEP framework is available, so the generic ACMG/AMP definition was considered. For a dominant disorder, BP2 requires observation of the assessed variant in trans with a pathogenic or likely pathogenic variant. The available case materials document the single variant NM_005359.6:c.463A>G (NP_005350.1:p.(Ser155Gly)) but provide no second pathogenic variant, family-level genotype data, or validated cis/trans phase information. Consequently, BP2 cannot be assessed from the available evidence and is not applied.
No reliable report was identified showing this exact variant in an affected individual who has an established alternate molecular basis for the relevant disease. The exact-variant paper extract reviewed for PMID:28655553 says the variant was not reported, and non-expert ClinVar classifications do not establish an alternate molecular diagnosis. The generic BP5 requirement therefore cannot be assessed.
Generic BP5: the variant is found in an affected individual with an alternate molecular basis for the disease; no applicable SMAD4-specific VCEP rule was available.
deterministic_prefilter: requires_null_variant_class
No SMAD4-specific VCEP framework is available, so the generic ACMG/AMP definition was considered. PM3 is intended for recessive disorders and requires evidence that the assessed variant occurs in trans with a pathogenic variant, or other biallelic disease evidence. The available SMAD4 disease context identifies hereditary hemorrhagic telangiectasia and juvenile polyposis as autosomal-dominant conditions, and the case contains no indication that this variant is being evaluated for a recessive SMAD4 disorder. Therefore PM3 is not applicable to this case; no biallelic pathogenic-variant evidence is used.
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
deterministic_prefilter: requires_repeat_region_indel
deterministic_prefilter: requires_synonymous
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 |
|---|
| East Asian1 / 44,822 | 2.2e-05 |
| African/African American1 / 74,706 | 1.3e-05 |
| European (non-Finnish)1 / 1,161,556 | 8.6e-07 |
| European (non-Finnish)1 / 113,664 | 8.8e-06 |
This variant is present in gnomAD v4.1 (AF= 1.88197e-06; MAF= 0.00019%, 3/1594076 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 2.23105e-05; MAF= 0.00223%, 1/44822 alleles, homozygotes = 0).
This variant is present in gnomAD v2.1 (AF= 3.9781e-06; MAF= 0.00040%, 1/251376 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.79786e-06; MAF= 0.00088%, 1/113664 alleles, homozygotes = 0).
Not available in gnomAD-Canada v1.0.
The variant is a missense substitution, NP_005350.1:p.(Ser155Gly), so the generic fallback requires the missense-specific REVEL path and does not substitute the splice-path SpliceAI result. REVEL is 0.484. This is below the supplied ClinGen SVI PP3 supporting threshold of >=0.644 (moderate >=0.773; strong >=0.932). BayesDel is not usable because no generic ACMG-strength calibration is established. Therefore PP3 is not met.
Generic ClinGen SVI missense calibration: REVEL >=0.644 for PP3 supporting, with higher thresholds for moderate and strong PP3.
The variant is a missense substitution, NP_005350.1:p.(Ser155Gly), so the generic fallback requires the missense-specific REVEL path and does not substitute the splice-path SpliceAI result. REVEL is 0.484. This is above the supplied ClinGen SVI BP4 supporting threshold of <=0.29 (moderate <=0.183; strong <=0.016). BayesDel is not usable because no generic ACMG-strength calibration is established. Therefore BP4 is not met.
Generic ClinGen SVI missense calibration: REVEL <=0.29 for BP4 supporting, with lower thresholds for moderate and strong BP4.
deterministic_prefilter: requires_synonymous
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06). REVEL score = 0.484. BayesDel score = -0.242868.
7 paper records listed. 1 cited in the classification. None of the listed paper records explicitly indicates that the variant is named.
The impact of a missense change depends on criteria such as the evolutionary conservation of an amino acid or nucleotide, the location and context within the protein sequence, and the biochemical consequence of the amino acid substitution.
Location Computational (In Silico) Predictive Programs
Context General ACMG/AMP workgroup consensus, surveys, workshop feedback, and review of variant-classification evidence; no SMAD4-specific cohort or assay described.
SMAD4 NM_005359.5 600993 Hereditary hemorrhagic telangiectasia/ juvenile polyposis AD
Table I, list of vascular-anomaly-associated genes analyzed
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= 1.88197e-06; MAF= 0.00019%, 3/1594076 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 2.23105e-05; MAF= 0.00223%, 1/44822 alleles, homozygotes = 0).
This variant is present in gnomAD v2.1 (AF= 3.9781e-06; MAF= 0.00040%, 1/251376 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.79786e-06; MAF= 0.00088%, 1/113664 alleles, homozygotes = 0).
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories) and as Uncertain Significance (1 clinical laboratory) and as Likely benign (1 clinical laboratory). (ClinVarID = 374977)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06). REVEL score = 0.484. BayesDel score = -0.242868.
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. SMAD4, a transcription factor in the TGFß pathway, is frequently mutated in pancreatic and colorectal cancers.
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.