rs747437716
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate
The NM_004329.3(BMPR1A):c.65A>C(p.Gln22Pro) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000311 in 1,609,416 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q22E) has been classified as Uncertain significance.
Frequency
Consequence
NM_004329.3 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BMPR1A | NM_004329.3 | c.65A>C | p.Gln22Pro | missense_variant, splice_region_variant | 3/13 | ENST00000372037.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BMPR1A | ENST00000372037.8 | c.65A>C | p.Gln22Pro | missense_variant, splice_region_variant | 3/13 | 1 | NM_004329.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152218Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251260Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135828
GnomAD4 exome AF: 6.86e-7 AC: 1AN: 1457198Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 725194
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152218Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74366
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 13, 2016 | This variant is denoted BMPR1A c.65A>C at the cDNA level, p.Gln22Pro (Q22P) at the protein level, and results in the change of a Glutamine to a Proline (CAA>CCA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BMPR1A Gln22Pro was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glutamine and Proline differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BMPR1A Gln22Pro occurs at a position that is not conserved and is located in the signal peptide region (Howe 2004, UniProt). While protein-based in silico analyses are inconsistent regarding the effect this variant may have on protein structure and function, multiple splicing models predict that this variant may lead to the creation of a cryptic splice acceptor site. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether BMPR1A Gln22Pro is pathogenic or benign. We consider it to be a variant of uncertain significance. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 04, 2021 | The p.Q22P variant (also known as c.65A>C), located in coding exon 1 of the BMPR1A gene, results from an A to C substitution at nucleotide position 65. The glutamine at codon 22 is replaced by proline, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Juvenile polyposis syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 14, 2023 | This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 22 of the BMPR1A protein (p.Gln22Pro). This variant is present in population databases (rs747437716, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with BMPR1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 421650). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at