ClinVar Miner

Submissions for variant NM_004329.2(BMPR1A):c.1166G>A (p.Ser389Asn) (rs879254049)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236250 SCV000293297 uncertain significance not provided 2015-10-22 criteria provided, single submitter clinical testing This variant is denoted BMPR1A c.1166G>A at the cDNA level, p.Ser389Asn (S389N) at the protein level, and results in the change of a Serine to an Asparagine (AGT>AAT). This variant has not, to our knowledge, been published in the literature as being pathogenic or benign. BMPR1A Ser389Asn was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Serine and Asparagine share similar properties, this is considered a conservative amino acid substitution. BMPR1A Ser389Asn occurs at a position that is conserved across species and is located in the MH1 domain and protein kinase domain (Howe 2004, UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether BMPR1A Ser389Asn is pathogenic or benign.
Invitae RCV000477534 SCV000552858 uncertain significance Juvenile polyposis syndrome 2017-12-20 criteria provided, single submitter clinical testing This sequence change replaces serine with asparagine at codon 389 of the BMPR1A protein (p.Ser389Asn). The serine residue is highly conserved and there is a small physicochemical difference between serine and asparagine. It also falls at the last nucleotide of exon 10 of the BMPR1A coding sequence. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a BMPR1A-related disease. ClinVar contains an entry for this variant (Variation ID: 246018). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of nucleotide changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a rare missense change with uncertain impact on mRNA splicing and protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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