rs730880216
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PM1PP2PP3PP5BS2
The ENST00000327367.9(SMAD3):c.1129G>A(p.Val377Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,614,058 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
ENST00000327367.9 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SMAD3 | NM_005902.4 | c.1129G>A | p.Val377Ile | missense_variant | 8/9 | ENST00000327367.9 | NP_005893.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SMAD3 | ENST00000327367.9 | c.1129G>A | p.Val377Ile | missense_variant | 8/9 | 1 | NM_005902.4 | ENSP00000332973 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152170Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251488Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135918
GnomAD4 exome AF: 0.0000109 AC: 16AN: 1461888Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9AN XY: 727246
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152170Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74332
ClinVar
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 28, 2023 | This missense variant replaces valine with isoleucine at codon 377 of the SMAD3 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). 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 been identified in 6/251488 chromosomes 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 04, 2023 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is not expected to disrupt SMAD3 function. ClinVar contains an entry for this variant (Variation ID: 180526). This missense change has been observed in individuals with clinical features of SMAD3-related conditions (Invitae). This variant is present in population databases (rs730880216, gnomAD 0.009%). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 377 of the SMAD3 protein (p.Val377Ile). - |
Arterial dissection;C0343190:Cutaneous polyarteritis nodosa Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Blueprint Genetics | Oct 17, 2014 | - - |
Aneurysm-osteoarthritis syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 30, 2023 | This missense variant replaces valine with isoleucine at codon 377 of the SMAD3 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 6/251488 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at