rs142292491
Variant summary
Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2
The NM_005359.6(SMAD4):c.21G>A(p.Thr7Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000102 in 1,613,538 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00011 ( 1 hom. )
Consequence
SMAD4
NM_005359.6 synonymous
NM_005359.6 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -2.36
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 -14 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.63).
BP6
Variant 18-51047067-G-A is Benign according to our data. Variant chr18-51047067-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 183887.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=9, Uncertain_significance=2, Benign=4}. Variant chr18-51047067-G-A is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=-2.36 with no splicing effect.
BS1
Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000105 (154/1461396) while in subpopulation NFE AF= 0.000129 (143/1111628). AF 95% confidence interval is 0.000111. There are 1 homozygotes in gnomad4_exome. There are 72 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
High AC in GnomAd4 at 11 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SMAD4 | NM_005359.6 | c.21G>A | p.Thr7Thr | synonymous_variant | 2/12 | ENST00000342988.8 | NP_005350.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SMAD4 | ENST00000342988.8 | c.21G>A | p.Thr7Thr | synonymous_variant | 2/12 | 5 | NM_005359.6 | ENSP00000341551.3 | ||
ENSG00000267699 | ENST00000590722.2 | n.*44G>A | non_coding_transcript_exon_variant | 3/9 | 2 | ENSP00000465737.1 | ||||
ENSG00000267699 | ENST00000590722.2 | n.*44G>A | 3_prime_UTR_variant | 3/9 | 2 | ENSP00000465737.1 |
Frequencies
GnomAD3 genomes AF: 0.0000723 AC: 11AN: 152142Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000637 AC: 16AN: 251310Hom.: 0 AF XY: 0.0000736 AC XY: 10AN XY: 135822
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GnomAD4 exome AF: 0.000105 AC: 154AN: 1461396Hom.: 1 Cov.: 31 AF XY: 0.0000990 AC XY: 72AN XY: 727038
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GnomAD4 genome AF: 0.0000723 AC: 11AN: 152142Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74314
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:17
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Benign:6
Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2023 | SMAD4: BP4, BP7 - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | - - |
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jan 02, 2018 | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome Uncertain:1Benign:2
Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | - - |
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. - |
Benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Apr 10, 2023 | This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. - |
Generalized juvenile polyposis/juvenile polyposis coli Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Counsyl | Nov 09, 2016 | - - |
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. - |
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 21, 2022 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Hereditary cancer-predisposing syndrome Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 21, 2016 | - - |
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Jan 03, 2022 | - - |
Myhre syndrome Benign:1
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. - |
SMAD4-related disorder Benign:1
Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | May 13, 2019 | 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 | Feb 04, 2015 | 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 30, 2024 | - - |
Computational scores
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Name
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