NM_004329.3:c.1511G>A

Variant names:

• chr10-86923631-G-A
• rs878854664
• NM_004329.3:c.1511G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_004329.3(BMPR1A):​c.1511G>A​(p.Trp504*) 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 NM_004329.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 10.0
• Publications: 1 publications found

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]

BMPR1A Gene-Disease associations (from GenCC):

• generalized juvenile polyposis/juvenile polyposis coli

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Genomics England PanelApp
• juvenile polyposis syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P
• polyposis syndrome, hereditary mixed, 2

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• hereditary mixed polyposis syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital heart defects, multiple types

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• pulmonary arterial hypertension

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 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 2 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 VariationId is 239856.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004329.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMPR1A	NM_004329.3	MANE Select	c.1511G>A	p.Trp504*	stop_gained	Exon 13 of 13	NP_004320.2
	BMPR1A	NM_001406559.1		c.1586G>A	p.Trp529*	stop_gained	Exon 14 of 14	NP_001393488.1
	BMPR1A	NM_001406560.1		c.1559G>A	p.Trp520*	stop_gained	Exon 14 of 14	NP_001393489.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMPR1A	ENST00000372037.8	TSL:1 MANE Select	c.1511G>A	p.Trp504*	stop_gained	Exon 13 of 13	ENSP00000361107.2
	BMPR1A	ENST00000480152.3	TSL:3	c.1511G>A	p.Trp504*	stop_gained	Exon 14 of 14	ENSP00000483569.2
	BMPR1A	ENST00000713672.1		c.1511G>A	p.Trp504*	stop_gained	Exon 12 of 12	ENSP00000518974.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Nov 18, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Dec 18, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been observed to segregate with juvenile polyposis in a family (Invitae). ClinVar contains an entry for this variant (Variation ID: 239856). For these reasons, this variant has been classified as Pathogenic. 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. 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 v4.9

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
PhyloP100		10
Vest4		0.79
GERP RS		5.9
Mutation Taster		=3/197	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs878854664; hg19: chr10-88683388; COSMIC: COSV100923696;