rs1555405092
Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong
The NM_005902.4(SMAD3):c.1A>C(p.Met1?) variant causes a initiator codon change. The variant allele was found at a frequency of 0.00000208 in 1,439,970 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_005902.4 initiator_codon
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SMAD3 | NM_005902.4 | c.1A>C | p.Met1? | initiator_codon_variant | Exon 1 of 9 | ENST00000327367.9 | NP_005893.1 | |
SMAD3 | NM_001407011.1 | c.1A>C | p.Met1? | initiator_codon_variant | Exon 1 of 10 | NP_001393940.1 | ||
SMAD3 | NM_001407012.1 | c.1A>C | p.Met1? | initiator_codon_variant | Exon 1 of 8 | NP_001393941.1 | ||
SMAD3 | NM_001407013.1 | c.1A>C | p.Met1? | initiator_codon_variant | Exon 1 of 8 | NP_001393942.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SMAD3 | ENST00000327367.9 | c.1A>C | p.Met1? | initiator_codon_variant | Exon 1 of 9 | 1 | NM_005902.4 | ENSP00000332973.4 | ||
SMAD3 | ENST00000560424.2 | c.1A>C | p.Met1? | initiator_codon_variant | Exon 1 of 10 | 3 | ENSP00000455540.2 | |||
SMAD3 | ENST00000559460.6 | c.-110+2211A>C | intron_variant | Intron 1 of 8 | 4 | ENSP00000453082.2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000208 AC: 3AN: 1439970Hom.: 0 Cov.: 33 AF XY: 0.00000280 AC XY: 2AN XY: 714348
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Pathogenic:2
The p.M1? variant (also known as c.1A>C), located in coding exon 1 of the SMAD3 gene, results from an A to C substitution at nucleotide position 1. This alters the methionine residue at the initiation codon. An alternate alteration in this codon, c.3G>A, has been reported in a child with hypoplastic left heart syndrome and aortic aneurysm, in his father with osteoarthritis and dilated aortic root, and in the proband's younger brother with no cardiac or osteoarthritis findings at the time of evaluation (Fitzgerald KK et al. Case Rep Genet, 2014 Mar;2014:591516). In addition to the clinical data presented in the literature, since sequence variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame, this variant is likely to be pathogenic. -
This sequence change affects the initiator methionine of the SMAD3 mRNA. The next in-frame methionine is located at codon 106. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individuals with spontaneous coronary artery dissection and/or thoracic aortic aneurysm and/or dissection (PMID: 29907982, 33125268; internal data). ClinVar contains an entry for this variant (Variation ID: 520186). This variant disrupts a region of the SMAD3 protein in which other variant(s) (p.Arg74Trp) have been determined to be pathogenic (PMID: 29510914, 31096651; internal data). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at