rs745672741
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PP3PP5_Very_Strong
The NM_005902.4(SMAD3):c.401-6G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
SMAD3
NM_005902.4 splice_region, splice_polypyrimidine_tract, intron
NM_005902.4 splice_region, splice_polypyrimidine_tract, intron
Scores
2
Splicing: ADA: 0.9984
2
Clinical Significance
Conservation
PhyloP100: 1.91
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 Likely_pathogenic. Variant got 9 ACMG points.
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 15-67165247-G-A is Pathogenic according to our data. Variant chr15-67165247-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 213782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-67165247-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SMAD3 | NM_005902.4 | c.401-6G>A | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ENST00000327367.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SMAD3 | ENST00000327367.9 | c.401-6G>A | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_005902.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1461870Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 727240
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1461870
Hom.:
Cov.:
34
AF XY:
AC XY:
0
AN XY:
727240
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:7
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 | Invitae | Dec 26, 2023 | This sequence change falls in intron 2 of the SMAD3 gene. It does not directly change the encoded amino acid sequence of the SMAD3 protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with thoracic aortic aneurysms and dissections (TAAD), and Aneurysms-Osteoarthritis Syndrome (OAS) (PMID: 25644172, 25877775; personal communication). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 213782). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 30, 2022 | The c.401-6G>A intronic variant results from a G to A substitution 6 nucleotides upstream from coding exon 3 in the SMAD3 gene. This variant has been reported in an individual with osteoarthritis and thoracic aortic aneurysm, as well as in several thoracic aortic aneurysm and dissection (TAAD) cohorts with limited clinical details (Koppen H et al. Headache, 2015 May;55:711-2; (Campens L et al. Orphanet J Rare Dis, 2015 Feb;10:9; Arnaud P et al. Genet Med, 2019 09;21:2015-2024; Hostetler EM et al. J Med Genet, 2019 04;56:252-260). RNA analysis confirmed the use of a cryptic acceptor site, which would lead to an out of frame sequence (Arnaud P et al. Genet Med, 2019 09;21:2015-2024). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice acceptor site. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
not provided Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Aneurysm-osteoarthritis syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 04, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | May 13, 2023 | - - |
Connective tissue disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Center for Human Genetics, Inc, Center for Human Genetics, Inc | Nov 01, 2016 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
Cadd
Uncertain
Dann
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: 2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at