rs137852751

Positions:

• chr2-202530820-C-T

Variant summary

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

The NM_001204.7(BMPR2):​c.994C>T​(p.Arg332Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000684 in 1,460,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BMPR2 NM_001204.7 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 4.00

Genes affected

BMPR2 (HGNC:1078): (bone morphogenetic protein receptor type 2) This gene encodes a member of the bone morphogenetic protein (BMP) receptor family of transmembrane serine/threonine kinases. The ligands of this receptor are members of the TGF-beta superfamily. BMPs are involved in endochondral bone formation and embryogenesis. These proteins transduce their signals through the formation of heteromeric complexes of two different types of serine (threonine) kinase receptors: type I receptors of about 50-55 kD and type II receptors of about 70-80 kD. Mutations in this gene have been associated with primary pulmonary hypertension, both familial and fenfluramine-associated, and with pulmonary venoocclusive disease. [provided by RefSeq, May 2020]

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 2-202530820-C-T is Pathogenic according to our data. Variant chr2-202530820-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 8810.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
BMPR2	NM_001204.7	c.994C>T	p.Arg332Ter	stop_gained	8/13	ENST00000374580.10	NP_001195.2
BMPR2	XM_011511687.2	c.994C>T	p.Arg332Ter	stop_gained	8/13		XP_011509989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BMPR2	ENST00000374580.10	c.994C>T	p.Arg332Ter	stop_gained	8/13	1	NM_001204.7	ENSP00000363708	P1
BMPR2	ENST00000374574.2	c.994C>T	p.Arg332Ter	stop_gained	8/12	2		ENSP00000363702

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460962 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726806

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 07, 2019	The R332X variant in the BMPR2 gene has been reported in multiple probands with either familial or sporadic pulmonary hypertension (Thomson et al., 2000; Sankelo et al., 2005; Rosenzweig et al., 2008; Portillo et al., 2010; Ghigna et al., 2016; Yang et al., 2018) and this variant segregated with disease in at least one family (Machado et al., 2001). Reduced penetrance has also been observed (Thomson et al., 2000; Machado et al., 2001). The R332X variant is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Other downstream nonsense variants in the BMPR2 gene have been reported in the Human Gene Mutation Database in association with PAH (Stenson et al., 2014), indicating that loss of function is an established disease mechanism. In addition, this variant is not observed in large population cohorts (Lek et al., 2016). -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 04, 2019	The BMPR2 c.994C>T; p.Arg332Ter variant (rs137852751) is reported in the literature in multiple individuals affected with pulmonary arterial hypertension (Elliott 2006, Ghinga 2016, Machado 2001, Sankelo 2005, Thomson 2000, Yang 2018). In two reports, this variant was also observed in several asymptomatic relatives of affected individuals, suggesting it may be incompletely penetrant (Machado 2001, Thomson 2000). The p.Arg332Ter variant is absent from general population databases (Genome Aggregation Database), indicating it is not a common polymorphism, and it is reported as pathogenic by several laboratories in ClinVar (Variation ID: 8810). This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, the p.Arg332Ter variant is considered to be pathogenic. References Elliott CG et al. Relationship of BMPR2 mutations to vasoreactivity in pulmonary arterial hypertension. Circulation. 2006 May 30;113(21):2509-15. Ghigna MR et al. BMPR2 mutation status influences bronchial vascular changes in pulmonary arterial hypertension. Eur Respir J. 2016 Dec;48(6):1668-1681. Machado RD et al. BMPR2 haploinsufficiency as the inherited molecular mechanism for primary pulmonary hypertension. Am J Hum Genet. 2001 Jan;68(1):92-102. Sankelo M et al. BMPR2 mutations have short lifetime expectancy in primary pulmonary hypertension. Hum Mutat. 2005 Aug;26(2):119-24. Thomson JR et al. Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-beta family. J Med Genet. 2000 Oct;37(10):741-5. Yang H et al. Genetic analyses in a cohort of 191 pulmonary arterial hypertension patients. Respir Res. 2018 May 9;19(1):87. -

Pulmonary hypertension, primary, 1 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2001	- -
Pathogenic, no assertion criteria provided	literature only	Rare Disease Genomics Group, St George's University of London	-	- -

Pulmonary arterial hypertension Pathogenic:1

Pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

-

- -

Primary pulmonary hypertension Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 28, 2024

This sequence change creates a premature translational stop signal (p.Arg332*) in the BMPR2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BMPR2 are known to be pathogenic (PMID: 16429395). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with pulmonary arterial hypertension (PMID: 11015450, 30578397). ClinVar contains an entry for this variant (Variation ID: 8810). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.94	D
MutationTaster	Benign	1.0	A;A
Vest4		0.91
GERP RS		4.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs137852751; hg19: chr2-203395543; COSMIC: COSV65808047;