rs863223420

Positions:

• chr2-202530955-G-A
• chr2-202530955-G-C
• chr2-202530955-G-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.1128+1G>A variant causes a splice donor 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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BMPR2 NM_001204.7 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 9.73

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: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 7.2, offset of 17, new splice context is: aagGTatca. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-202530955-G-A is Pathogenic according to our data. Variant chr2-202530955-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 212811.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.1128+1G>A		splice_donor_variant		ENST00000374580.10	NP_001195.2
BMPR2	XM_011511687.2	c.1128+1G>A		splice_donor_variant			XP_011509989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BMPR2	ENST00000374580.10	c.1128+1G>A		splice_donor_variant		1	NM_001204.7	ENSP00000363708	P1
BMPR2	ENST00000374574.2	c.1128+1G>A		splice_donor_variant		2		ENSP00000363702

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 22, 2015	c.1128+1 G>A: IVS8+1 G>A in exon 8 of the BMPR2 gene (NM_001204.6). The c.1128+1 G>A mutation has been reported in at least one individual with idiopathic PAH (Machado et al., 2006). Additionally, a substitution at this same position (c.1128+1 G>T) has been reported in at least three individuals with PAH and was absent from 60 healthy control individuals (Rinderman et al., 2003; Cogan et al., 2006; Machado et al., 2006). This mutation destroys the canonical splice donor site in intron 8 and is predicted to cause abnormal gene splicing. The mutation is predicted to lead to either an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Other splice site mutations in the BMPR2 gene have been reported in association with PAH. In summary, c.1128+1 G>A in the BMPR2 gene is interpreted as a disease-causing mutation. This variant was found in BMPR2,PAH-ARRHYTHMIA -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 12, 2019	The BMPR2 c.1128+1G>A variant (rs863223420) is reported in the literature in individuals affected with idiopathic pulmonary arterial hypertension (Machado 2006, Wang 2019), and a similar variant with a different nucleotide change, c.1128+1G>T, was also reported in two affected families (Cogan 2006, Koelher 2004, Pfarr 2011, Rindermann 2003). The c.1128+1G>A variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 212811), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant disrupts the canonical splice donor site of intron 8. Functional assays show that the c.1128+1G>T variant results in a stable transcript with an in-frame skipping of exons 8 and 9 (Cogan 2006). Based on available information, the c.1128+1G>A variant is considered to be pathogenic. REFERENCES Cogan DJ et al. High frequency of BMPR2 exonic deletions/duplications in familial pulmonary arterial hypertension. Am J Respir Crit Care Med. 2006 Sep 1;174(5):590-8. Koehler R et al. Low frequency of BMPR2 mutations in a German cohort of patients with sporadic idiopathic pulmonary arterial hypertension. J Med Genet. 2004 Dec;41(12):e127. Machado RD et al. Mutations of the TGF-b type II receptor BMPR2 in pulmonary arterial hypertension. Hum Mutat. 2006 Feb;27(2):121-32. Pfarr N et al. Hemodynamic and clinical onset in patients with hereditary pulmonary arterial hypertension and BMPR2 mutations. Respir Res. 2011 Jul 29;12:99. Rindermann M et al. Primary pulmonary hypertension may be a heterogeneous disease with a second locus on chromosome 2q31. J Am Coll Cardiol. 2003 Jun 18;41(12):2237-44. Wang XJ et al. Germline BMP9 mutation causes idiopathic pulmonary arterial hypertension. Eur Respir J. 2019 Mar 14;53(3). pii: 1801609. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 15, 2015	- -

Primary pulmonary hypertension Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 22, 2023

This sequence change affects a donor splice site in intron 8 of the BMPR2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BMPR2 are known to be pathogenic (PMID: 16429395). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with pulmonary arterial hypertension (PMID: 16429395). ClinVar contains an entry for this variant (Variation ID: 212811). 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. -

Pulmonary hypertension, primary, 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Rare Disease Genomics Group, St George's University of London

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Pulmonary arterial hypertension;C5679820:Idiopathic and/or familial pulmonary arterial hypertension Other:1

not provided, no classification provided

literature only

Wendy Chung Laboratory, Columbia University Medical Center

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D
GERP RS		5.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.95		Position offset: 16
DS_DL_spliceai		1.0		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs863223420; hg19: chr2-203395678;