18-51048865-G-A
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Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2
The NM_005359.6(SMAD4):c.424+5G>A variant causes a splice region, intron change. The variant allele was found at a frequency of 0.000185 in 1,608,638 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00019 ( 0 hom. )
Consequence
SMAD4
NM_005359.6 splice_region, intron
NM_005359.6 splice_region, intron
Scores
2
Splicing: ADA: 0.9973
2
Clinical Significance
Conservation
PhyloP100: 5.70
Genes affected
SMAD4 (HGNC:6770): (SMAD family member 4) This gene encodes a member of the Smad family of signal transduction proteins. Smad proteins are phosphorylated and activated by transmembrane serine-threonine receptor kinases in response to transforming growth factor (TGF)-beta signaling. The product of this gene forms homomeric complexes and heteromeric complexes with other activated Smad proteins, which then accumulate in the nucleus and regulate the transcription of target genes. This protein binds to DNA and recognizes an 8-bp palindromic sequence (GTCTAGAC) called the Smad-binding element (SBE). The protein acts as a tumor suppressor and inhibits epithelial cell proliferation. It may also have an inhibitory effect on tumors by reducing angiogenesis and increasing blood vessel hyperpermeability. The encoded protein is a crucial component of the bone morphogenetic protein signaling pathway. The Smad proteins are subject to complex regulation by post-translational modifications. Mutations or deletions in this gene have been shown to result in pancreatic cancer, juvenile polyposis syndrome, and hereditary hemorrhagic telangiectasia syndrome. [provided by RefSeq, May 2022]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -9 ACMG points.
BP6
Variant 18-51048865-G-A is Benign according to our data. Variant chr18-51048865-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127950.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=6, Benign=2, Likely_benign=10}. Variant chr18-51048865-G-A is described in Lovd as [Benign]. Variant chr18-51048865-G-A is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000125 (19/151952) while in subpopulation SAS AF= 0.000621 (3/4834). AF 95% confidence interval is 0.000169. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 19 AD gene.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| SMAD4 | NM_005359.6 | c.424+5G>A | splice_region_variant, intron_variant | Intron 3 of 11 | ENST00000342988.8 | NP_005350.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| SMAD4 | ENST00000342988.8 | c.424+5G>A | splice_region_variant, intron_variant | Intron 3 of 11 | 5 | NM_005359.6 | ENSP00000341551.3 | |||
| ENSG00000267699 | ENST00000590722.2 | n.*447+5G>A | splice_region_variant, intron_variant | Intron 4 of 8 | 2 | ENSP00000465737.1 |
Frequencies
GnomAD3 genomes 0.000125 AC: 19AN: 151834Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000219 AC: 55AN: 250792Hom.: 0 AF XY: 0.000229 AC XY: 31AN XY: 135584
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GnomAD4 exome AF: 0.000191 AC: 278AN: 1456686Hom.: 0 Cov.: 31 AF XY: 0.000212 AC XY: 154AN XY: 724816
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GnomAD4 genome 0.000125 AC: 19AN: 151952Hom.: 0 Cov.: 33 AF XY: 0.000135 AC XY: 10AN XY: 74308
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:6Benign:15
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:2Benign:4
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 11, 2025 | In silico analysis supports that this variant does not alter splicing; however, published functional studies demonstrate evidence of aberrant splicing (Shiraishi Y et al. Systematic identification of intron retention associated variants from massive publicly available transcriptome sequencing data. bioRxiv. October 7, 2021); Observed in individuals with Lynch syndrome-associated cancer, familial gastric cancer, pancreatic cancer, breast cancer, or polyps, but has not been published in individuals with connective tissue disorders to our knowledge (PMID: 25186627, 27146957, 28726808, 30426508, 32066632, 34326862, 35534704); This variant is associated with the following publications: (PMID: 32066632, 25980754, 28873162, 31159747, 27146957, Shiraishi2021, 25186627, 28726808, 30426508, 35534704, 34326862) - |
| Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Apr 19, 2023 | The frequency of this variant in the general population, 0.00037 (47/128762 chromosomes in European (Non-Finnish) subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in individuals with breast and/or ovarian cancer (PMIDs: 31159747 (2019), 30426508 (2018), and 25186627 (2015)), pancreatic cancer (PMID: 28726808 (2018)), gastric cancer (PMID: 32066632 (2021)), colon cancer (PMID: 25980754 (2015)), and hamartomatous polyposis syndrome (PMID: 2714957 (2016)). Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper SMAD4 mRNA splicing . Based on the available information, we are unable to determine the clinical significance of this variant. - |
| Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jan 31, 2021 | The SMAD4 c.424+5G>A variant (rs200772603) is reported in the literature in an individual with suspected Lynch syndrome (Yurgelun 2015) and another individual referred for hereditary cancer testing (Tsaousis 2019). This variant is found in the non-Finnish European population with an overall allele frequency of 0.04% (47/128762 alleles) in the Genome Aggregation Database. This is an intronic variant in a highly conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical donor splice site. However, given the lack of clinical and functional data, the significance of the c.424+5G>A variant is uncertain at this time. References: Tsaousis et al. Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations. BMC Cancer. 2019 Jun 3;19(1):535. Yurgelun MB et al. Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome. Gastroenterology. 2015 Sep;149(3):604-13.e20. - |
| Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2025 | SMAD4: BP4, BS2 - |
| Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
not specified Uncertain:1Benign:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Mar 04, 2025 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 03, 2024 | Variant summary: SMAD4 c.424+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant weakens a 5' donor site. One predict the variant abolishes a 5 splicing donor site. One predict the variant no significant impact on splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00022 in 250792 control chromosomes. The observed variant frequency is approximately 110 fold of the estimated maximal expected allele frequency for a pathogenic variant in SMAD4 causing Juvenile Polyposis Syndrome phenotype (2e-06), strongly suggesting that the variant is benign. c.424+5G>A has been reported in the literature in individuals affected with cancer including colorectal cancer, hereditary breast and ovarian cancer, pancreatic ductal adenocarcinoma and familial intestinal gastric cancer (e.g. Tung_2015, Yurgelun_2015, Mandelker_2017, Chaffee_2018, Schubert_2019, Tsaousis_2019, Carvalho_2021). These reports do not provide unequivocal conclusions about association of the variant with Juvenile Polyposis Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25980754, 25186627, 27146957, 28873162, 28726808, 30426508, 31159747, 32066632). ClinVar contains an entry for this variant (Variation ID: 127950). Based on the evidence outlined above, the variant was classified as likely benign. - |
| Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Aug 31, 2021 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:2
| Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 17, 2020 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneKor MSA | Aug 01, 2018 | - - |
| Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Nov 12, 2020 | - - |
Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome Uncertain:1Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Apr 10, 2023 | This variant is considered likely benign. This variant is intronic and is not expected to impact mRNA splicing. Homozygosity has been confirmed in one or more individuals. As homozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality, this variant is unlikely to be pathogenic. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Generalized juvenile polyposis/juvenile polyposis coli Benign:2
| Likely benign, criteria provided, single submitter | clinical testing | Counsyl | May 23, 2018 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Nov 25, 2016 | - - |
Myhre syndrome Benign:1
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
SMAD4-related disorder Benign:1
| Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 10, 2024 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Hereditary cancer-predisposing syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 24, 2019 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Juvenile polyposis syndrome Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 28, 2025 | - - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Uncertain
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at