rs587776881
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_005902.4(SMAD3):c.653del(p.Asn218ThrfsTer23) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
SMAD3
NM_005902.4 frameshift
NM_005902.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.40
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 Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 15-67170597-TA-T is Pathogenic according to our data. Variant chr15-67170597-TA-T is described in ClinVar as [Pathogenic]. Clinvar id is 30309.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-67170597-TA-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SMAD3 | NM_005902.4 | c.653del | p.Asn218ThrfsTer23 | frameshift_variant | 5/9 | ENST00000327367.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SMAD3 | ENST00000327367.9 | c.653del | p.Asn218ThrfsTer23 | frameshift_variant | 5/9 | 1 | NM_005902.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 11, 2020 | The c.653delA pathogenic mutation, located in coding exon 5 of the SMAD3 gene, results from a deletion of one nucleotide at nucleotide position 653, causing a translational frameshift with a predicted alternate stop codon (p.N218Tfs*23). This mutation segregated with vascular disease in a large family with thoracic aortic aneurysm and dissection (TAAD), intracranial aneurysms (ICA), abdominal aortic aneurysms (AAA), and bilateral iliac aneurysms (Regalado ES et al. Circ. Res., 2011 Sep;109:680-6; Hostetler EM et al. J. Med. Genet., 2019 04;56:252-260). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 31, 2018 | For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in SMAD3 are known to be pathogenic (PMID: 21778426, 24804794). This variant has been observed to segregate with thoracic aortic aneurysm and dissection in a family (PMID: 21778426). ClinVar contains an entry for this variant (Variation ID: 30309). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Asn218Thrfs*23) in the SMAD3 gene. It is expected to result in an absent or disrupted protein product. - |
Aneurysm-osteoarthritis syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 02, 2011 | - - |
Computational scores
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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