rs587781928
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_004329.3(BMPR1A):c.826_827del(p.Glu276AsnfsTer10) variant causes a frameshift change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T275T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
BMPR1A
NM_004329.3 frameshift
NM_004329.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 10.0
Genes affected
BMPR1A (HGNC:1076): (bone morphogenetic protein receptor type 1A) The bone morphogenetic protein (BMP) receptors are a family of transmembrane serine/threonine kinases that include the type I receptors BMPR1A and BMPR1B and the type II receptor BMPR2. These receptors are also closely related to the activin receptors, ACVR1 and ACVR2. The ligands of these receptors are members of the TGF-beta superfamily. TGF-betas and activins transduce their signals through the formation of heteromeric complexes with 2 different types of serine (threonine) kinase receptors: type I receptors of about 50-55 kD and type II receptors of about 70-80 kD. Type II receptors bind ligands in the absence of type I receptors, but they require their respective type I receptors for signaling, whereas type I receptors require their respective type II receptors for ligand binding. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
?
Variant 10-86917282-CAG-C is Pathogenic according to our data. Variant chr10-86917282-CAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 141674.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86917282-CAG-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BMPR1A | NM_004329.3 | c.826_827del | p.Glu276AsnfsTer10 | frameshift_variant | 9/13 | ENST00000372037.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BMPR1A | ENST00000372037.8 | c.826_827del | p.Glu276AsnfsTer10 | frameshift_variant | 9/13 | 1 | NM_004329.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 10, 2014 | The c.826_827delGA pathogenic mutation, located in coding exon 7 of the BMPR1A gene, results from a deletion of two nucleotides between nucleotide positions 826 and 827, causing a translational frameshift with a predicted alternate stop codon. This mutation has been identified in one family with juvenile polyposis syndrome and colon cancer (Zhou XP et al. Am. J. Hum. Genet. 2001; 69:704-11). In addition to the clinical data presented in the literature, since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). - |
Juvenile polyposis syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 30, 2020 | Loss-of-function variants in BMPR1A are known to be pathogenic (PMID: 11536076, 12417513). For these reasons, this variant has been classified as Pathogenic. This variant has been reported in an individual with colon cancer and a family history of juvenile polyps (PMID: 11536076). ClinVar contains an entry for this variant (Variation ID: 141674). This sequence change creates a premature translational stop signal (p.Glu276Asnfs*10) in the BMPR1A gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). - |
Computational scores
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at