rs1085307330

Variant names:

• chr2-202532736-A-G
• rs1085307330
• NM_001204.7:c.1276+4A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The BMPR2 c.1276+4A>G variant is a non-canonical splice site (+4) variant located in intron 9. The variant is absent from gnomAD v.2.1.1 and v4.1.0 (PM2_supporting) and was reported in a single proband with PAH (PMID:16429395). An in vitro exon trapping assay (including wild-type exon 9, or missense or c.1267+4A>G mutant exon 9) demonstrated exon skipping with the non-canonical splice variant (PMID:18321866). Further, in silico prediction (SpliceAI = 0.59) indicates the variant will probably impact splicing with loss of the canonical donor site in intron 9. Exon skipping or use of a cryptic splice site would lead to nonsense-mediated decay or disrupt the region encoding the conserved intracellular kinase domain, respectively. Taken together, the data support the application of PVS1 instead of PP3 and PM1 (PMID:37352859). No familial segregation data were available. In summary, the variant meets the criteria to be classified as likely pathogenic for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PVS1, PM2_supporting, (VCEP specification version v1.1, 1/18/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA645293835/MONDO:0015924/125

• Frequency: Genomes: not found (cov: 31)
• Consequence: BMPR2 NM_001204.7 splice_region, intron
• Scores: Splicing: ADA: 0.7481
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 2.33
• Publications: 0 publications found

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]

BMPR2 Gene-Disease associations (from GenCC):

• pulmonary arterial hypertension

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• pulmonary hypertension, primary, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• heritable pulmonary arterial hypertension

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMPR2	NM_001204.7	c.1276+4A>G		splice_region_variant, intron_variant	Intron 9 of 12	ENST00000374580.10	NP_001195.2
BMPR2	XM_011511687.2	c.1276+4A>G		splice_region_variant, intron_variant	Intron 9 of 12		XP_011509989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMPR2	ENST00000374580.10	c.1276+4A>G		splice_region_variant, intron_variant	Intron 9 of 12	1	NM_001204.7	ENSP00000363708.4
BMPR2	ENST00000374574.2	c.1276+4A>G		splice_region_variant, intron_variant	Intron 9 of 11	2		ENSP00000363702.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Pulmonary arterial hypertension Pathogenic:1

Apr 29, 2025

Clingen Pulmonary Hypertension Variant Curation Expert Panel, ClinGen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The BMPR2 c.1276+4A>G variant is a non-canonical splice site (+4) variant located in intron 9. The variant is absent from gnomAD v.2.1.1 and v4.1.0 (PM2_supporting) and was reported in a single proband with PAH (PMID: 16429395). An in vitro exon trapping assay (including wild-type exon 9, or missense or c.1267+4A>G mutant exon 9) demonstrated exon skipping with the non-canonical splice variant (PMID: 18321866). Further, in silico prediction (SpliceAI = 0.59) indicates the variant will probably impact splicing with loss of the canonical donor site in intron 9. Exon skipping or use of a cryptic splice site would lead to nonsense-mediated decay or disrupt the region encoding the conserved intracellular kinase domain, respectively. Taken together, the data support the application of PVS1 instead of PP3 and PM1 (PMID: 37352859). No familial segregation data were available. In summary, the variant meets the criteria to be classified as likely pathogenic for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PVS1, PM2_supporting, (VCEP specification version v1.1, 1/18/2024). -

Pulmonary hypertension, primary, 1 Pathogenic:1

-

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	12
DANN	Benign	0.95
PhyloP100		2.3
Mutation Taster		=17/83	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.75
dbscSNV1_RF	Benign	0.56
SpliceAI score (max)		0.59		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.59		Position offset: -4

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

Other links and lift over

dbSNP: rs1085307330; hg19: chr2-203397459;