chr18-51078478-C-T
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Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_005359.6(SMAD4):c.*11C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00618 in 1,588,848 control chromosomes in the GnomAD database, including 61 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0052 ( 6 hom., cov: 32)
Exomes 𝑓: 0.0063 ( 55 hom. )
Consequence
SMAD4
NM_005359.6 3_prime_UTR
NM_005359.6 3_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.135
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 -20 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.89).
BP6
Variant 18-51078478-C-T is Benign according to our data. Variant chr18-51078478-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 139220.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-51078478-C-T is described in Lovd as [Benign]. Variant chr18-51078478-C-T is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00524 (798/152264) while in subpopulation AMR AF= 0.0083 (127/15298). AF 95% confidence interval is 0.00748. There are 6 homozygotes in gnomad4. There are 384 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 798 AD gene.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| SMAD4 | NM_005359.6 | c.*11C>T | 3_prime_UTR_variant | 12/12 | ENST00000342988.8 | NP_005350.1 | ||
| SMAD4 | NM_001407041.1 | c.*11C>T | 3_prime_UTR_variant | 12/12 | NP_001393970.1 | |||
| SMAD4 | NM_001407042.1 | c.*11C>T | 3_prime_UTR_variant | 12/12 | NP_001393971.1 | |||
| SMAD4 | NR_176265.1 | n.2321C>T | non_coding_transcript_exon_variant | 13/13 |
Ensembl
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GnomAD3 genomes 0.00524 AC: 798AN: 152146Hom.: 6 Cov.: 32
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GnomAD3 exomes AF: 0.00519 AC: 1296AN: 249762Hom.: 6 AF XY: 0.00500 AC XY: 675AN XY: 134998
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GnomAD4 exome AF: 0.00628 AC: 9027AN: 1436584Hom.: 55 Cov.: 26 AF XY: 0.00616 AC XY: 4412AN XY: 716332
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GnomAD4 genome 0.00524 AC: 798AN: 152264Hom.: 6 Cov.: 32 AF XY: 0.00516 AC XY: 384AN XY: 74456
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:17
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:8
| Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 21, 2023 | - - |
| Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jul 26, 2018 | - - |
| Benign, criteria provided, single submitter | clinical testing | GeneDx | Nov 07, 2013 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
| Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
| Benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
| Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
| Likely benign, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | - | - - |
not provided Benign:3
| Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Apr 15, 2022 | - - |
| Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
| Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2024 | SMAD4: BS1, BS2 - |
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. - |
Carcinoma of colon Benign:1
| Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The SMAD4 c.*11C>T variant was not identified in the literature nor was it identified in the ARUP Laboratories database. The variant was identified in dbSNP (ID: rs11663402) as "With other allele", ClinVar (classified as benign by Color Genomics, GeneDx, and PreventionGenetics; as likely benign by Mayo Clinic), and LOVD 3.0 (3x benign or likely benign). The variant was identified in control databases in 1416 of 275456 chromosomes (8 homozygous) at a frequency of 0.005, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 37 of 23968 chromosomes (freq: 0.002), Other in 30 of 6442 chromosomes (freq: 0.005), Latino in 177 of 34334 chromosomes (freq: 0.005), European in 987 of 125862 chromosomes (freq: 0.008), Ashkenazi Jewish in 71 of 10094 chromosomes (freq: 0.007), Finnish in 97 of 25220 chromosomes (freq: 0.004), and South Asian in 17 of 30714 chromosomes (freq: 0.0006), but was not observed in the East Asian population. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. - |
Familial thoracic aortic aneurysm and aortic dissection Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Mar 09, 2017 | - - |
Generalized juvenile polyposis/juvenile polyposis coli 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. - |
Hereditary cancer-predisposing syndrome Benign:1
| Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 09, 2016 | - - |
Juvenile polyposis/hereditary hemorrhagic telangiectasia 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. - |
Computational scores
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Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at