chr15-67066155-A-T
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>T(p.Met1?) variant causes a initiator codon change. The variant allele was found at a frequency of 0.00000139 in 1,439,974 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>T | p.Met1? | initiator_codon_variant | Exon 1 of 9 | ENST00000327367.9 | NP_005893.1 | |
SMAD3 | NM_001407011.1 | c.1A>T | p.Met1? | initiator_codon_variant | Exon 1 of 10 | NP_001393940.1 | ||
SMAD3 | NM_001407012.1 | c.1A>T | p.Met1? | initiator_codon_variant | Exon 1 of 8 | NP_001393941.1 | ||
SMAD3 | NM_001407013.1 | c.1A>T | 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>T | p.Met1? | initiator_codon_variant | Exon 1 of 9 | 1 | NM_005902.4 | ENSP00000332973.4 | ||
SMAD3 | ENST00000560424.2 | c.1A>T | p.Met1? | initiator_codon_variant | Exon 1 of 10 | 3 | ENSP00000455540.2 | |||
SMAD3 | ENST00000559460.6 | c.-110+2211A>T | intron_variant | Intron 1 of 8 | 4 | ENSP00000453082.2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000139 AC: 2AN: 1439974Hom.: 0 Cov.: 33 AF XY: 0.00000140 AC XY: 1AN XY: 714350
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Aneurysm-osteoarthritis syndrome Pathogenic:2
The variant NM_005902.4:c.1A>T (chr15:67066155) in SMAD3 was detected in 2 heterozygotes out of 58K WGS Icelanders (MAF= 0,002%). This variant has been reported in ClinVar previously as likely pathogenic. Based on ACMG criteria (PVS1, PP5) this variant classifies as likely pathogenic. -
This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2. -
Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
This sequence change affects the initiator methionine of the SMAD3 mRNA. The next in-frame methionine is located at codon 106. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has been observed in individuals affected with thoracic aortic aneurysm and/or dissection or arterial dissection (PMID: 29907982, 33125268 , Invitae). This variant disrupts the initiator methionine in SMAD3. If translation initiates from the next in-frame methionine, the SMAD3 protein would no longer include the region containing the p.Arg93 amino acid residue. Other variant(s) that disrupt this residue have been observed in individuals with SMAD3-related conditions (PMID: 29543232, Invitae), which suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this allele has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at