rs878854664

Positions:

• chr10-86923631-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The ENST00000372037.8(BMPR1A):​c.1511G>A​(p.Trp504Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BMPR1A ENST00000372037.8 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• 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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.055 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-86923631-G-A is Pathogenic according to our data. Variant chr10-86923631-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 239856.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BMPR1A	NM_004329.3	c.1511G>A	p.Trp504Ter	stop_gained	13/13	ENST00000372037.8	NP_004320.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BMPR1A	ENST00000372037.8	c.1511G>A	p.Trp504Ter	stop_gained	13/13	1	NM_004329.3	ENSP00000361107	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 18, 2022

The p.W504* pathogenic mutation (also known as c.1511G>A), located in coding exon 11 of the BMPR1A gene, results from a G to A substitution at nucleotide position 1511. This changes the amino acid from a tryptophan to a stop codon within coding exon 11. This mutation was identified in two individuals both of whom had a history of juvenile colon polyps (Ambry internal data). In addition to the clinical data, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation. -

Juvenile polyposis syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 18, 2018

This variant leads to the truncation of the last 29 amino acids of the BMPR1A protein, including the loss of the C-terminal portion of the kinase domain (PMID: 8397373). However, experimental studies and prediction algorithms are not available for this variant, and the functional significance of the affected amino acids is currently unknown. For these reasons, this variant has been classified as Pathogenic. This variant has been observed to segregate with juvenile polyposis in a family (Invitae). ClinVar contains an entry for this variant (Variation ID: 239856). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the BMPR1A gene (p.Trp504*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 29 amino acids of the BMPR1A protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	43
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D
Vest4		0.79
GERP RS		5.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs878854664; hg19: chr10-88683388; COSMIC: COSV100923696;