rs876660442

chr10-86899863-C-CA

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_004329.3(BMPR1A):c.405dup(p.Pro136ThrfsTer13) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q135Q) 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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 6.22

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-86899863-C-CA is Pathogenic according to our data. Variant chr10-86899863-C-CA is described in ClinVar as [Pathogenic]. Clinvar id is 233491.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BMPR1A	NM_004329.3	c.405dup	p.Pro136ThrfsTer13	frameshift_variant	6/13	ENST00000372037.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMPR1A	ENST00000372037.8	c.405dup	p.Pro136ThrfsTer13	frameshift_variant	6/13	1	NM_004329.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Juvenile polyposis syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 26, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	May 03, 2023	The c.405dup (p.Pro136Thrfs*13) variant of the BMPR1A gene results in a premature termination codon that is predicted to lead to an absent or truncated protein product. Loss of function variants in BMPR1A are known to be pathogenic (PMID: 11381269, 15235019, 23399955, 11536076, 12417513). This variant has been reported in one individual with Juvenile Polyposis Syndrome (PMID: 16436638). Truncating variants downstream of this variant are reported to be pathogenic in the literature (PMID: 17873119) and by several ClinVar submitters (ClinVar ID: 1738567, 835681, 429099, 1750141). This variant is absent in the general population database (gnomAD). Therefore, the c.405dup (p.Pro136Thrfs*13) variant in the BMPR1A gene is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 18, 2023	This sequence change creates a premature translational stop signal (p.Pro136Thrfs*13) in the BMPR1A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BMPR1A are known to be pathogenic (PMID: 11536076, 12417513). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of juvenile polyposis syndrome (PMID: 16436638). ClinVar contains an entry for this variant (Variation ID: 233491). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 27, 2023	This variant inserts 1 nucleotide in exon 6 of the BMPR1A gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in an individual affected with juvenile polyposis syndrome (PMID: 16436638). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BMPR1A function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 14, 2021	The c.405dupA pathogenic mutation, located in coding exon 4 of the BMPR1A gene, results from a duplication of A at nucleotide position 405, causing a translational frameshift with a predicted alternate stop codon (p.P136Tfs*13). This mutation has been previously identified in an individual with a clinical diagnosis of juvenile polyposis syndrome (JPS) (Pyatt RE, et al. J Mol Diagn 2006 Feb; 8(1):84-8). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs876660442; hg19: chr10-88659620;