15-67066150-C-A
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_005902.4(SMAD3):c.-5C>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 0.00000315 in 1,586,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000028 ( 0 hom. )
Consequence
SMAD3
NM_005902.4 5_prime_UTR
NM_005902.4 5_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: 1.73
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_benign. Variant got -2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.55).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SMAD3 | NM_005902.4 | c.-5C>A | 5_prime_UTR_variant | 1/9 | ENST00000327367.9 | ||
SMAD3 | NM_001407011.1 | c.-5C>A | 5_prime_UTR_variant | 1/10 | |||
SMAD3 | NM_001407012.1 | c.-5C>A | 5_prime_UTR_variant | 1/8 | |||
SMAD3 | NM_001407013.1 | c.-5C>A | 5_prime_UTR_variant | 1/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SMAD3 | ENST00000327367.9 | c.-5C>A | 5_prime_UTR_variant | 1/9 | 1 | NM_005902.4 | P1 | ||
SMAD3 | ENST00000560424.2 | c.-5C>A | 5_prime_UTR_variant | 1/10 | 3 | ||||
SMAD3 | ENST00000559460.6 | c.-110+2206C>A | intron_variant | 4 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152012Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000279 AC: 4AN: 1434660Hom.: 0 Cov.: 32 AF XY: 0.00000422 AC XY: 3AN XY: 711350
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GnomAD4 genome AF: 0.00000658 AC: 1AN: 152012Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74242
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Aneurysm-osteoarthritis syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | May 04, 2023 | This variant changes a single nucleotide in the 5' untranslated region of the SMAD3 gene. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with SMAD3-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
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