rs1061427
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Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1
The NM_005902.4(SMAD3):c.-15G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.234 in 1,567,362 control chromosomes in the GnomAD database, including 44,612 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.22 ( 3864 hom., cov: 31)
Exomes 𝑓: 0.24 ( 40748 hom. )
Consequence
SMAD3
NM_005902.4 5_prime_UTR
NM_005902.4 5_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.354
Genes affected
SMAD3 (HGNC:6769): (SMAD family member 3) The SMAD family of proteins are a group of intracellular signal transducer proteins similar to the gene products of the Drosophila gene 'mothers against decapentaplegic' (Mad) and the C. elegans gene Sma. The SMAD3 protein functions in the transforming growth factor-beta signaling pathway, and transmits signals from the cell surface to the nucleus, regulating gene activity and cell proliferation. This protein forms a complex with other SMAD proteins and binds DNA, functioning both as a transcription factor and tumor suppressor. Mutations in this gene are associated with aneurysms-osteoarthritis syndrome and Loeys-Dietz Syndrome 3. [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=-0.6).
BP6
?
Variant 15-67066140-G-A is Benign according to our data. Variant chr15-67066140-G-A is described in ClinVar as [Benign]. Clinvar id is 139216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-67066140-G-A is described in Lovd as [Benign].
BA1
?
GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.292 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SMAD3 | NM_005902.4 | c.-15G>A | 5_prime_UTR_variant | 1/9 | ENST00000327367.9 | ||
SMAD3 | NM_001407011.1 | c.-15G>A | 5_prime_UTR_variant | 1/10 | |||
SMAD3 | NM_001407012.1 | c.-15G>A | 5_prime_UTR_variant | 1/8 | |||
SMAD3 | NM_001407013.1 | c.-15G>A | 5_prime_UTR_variant | 1/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SMAD3 | ENST00000327367.9 | c.-15G>A | 5_prime_UTR_variant | 1/9 | 1 | NM_005902.4 | P1 | ||
SMAD3 | ENST00000560424.2 | c.-15G>A | 5_prime_UTR_variant | 1/10 | 3 | ||||
SMAD3 | ENST00000559460.6 | c.-110+2196G>A | intron_variant | 4 |
Frequencies
GnomAD3 genomes ? AF: 0.223 AC: 33775AN: 151458Hom.: 3870 Cov.: 31
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GnomAD3 exomes AF: 0.232 AC: 41473AN: 178506Hom.: 5242 AF XY: 0.241 AC XY: 23287AN XY: 96594
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GnomAD4 exome AF: 0.235 AC: 333285AN: 1415792Hom.: 40748 Cov.: 32 AF XY: 0.238 AC XY: 167045AN XY: 700466
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GnomAD4 genome ? AF: 0.223 AC: 33763AN: 151570Hom.: 3864 Cov.: 31 AF XY: 0.226 AC XY: 16695AN XY: 74032
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ClinVar
Significance: Benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:4
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 04, 2013 | -15G>A in exon 1 of SMAD3: This variant is not expected to have clinical signifi cance because it has been identified in 22.8% (1943/8510) of European American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washing - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Nov 13, 2012 | 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, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 16, 2019 | - - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Familial thoracic aortic aneurysm and aortic dissection Benign:2
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 19, 2018 | - - |
Aneurysm-osteoarthritis 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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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at