rs137852744

Variant names:

• chr2-202530866-G-A
• rs137852744
• NM_001204.7:c.1040G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PS4 PS3_Supporting PM5_Supporting PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_001204.7(BMPR2) c.1040A>C variant is a missense variant predicted to cause substitution of cysteine by tyrosine at amino acid 347 (p.Cys347Tyr). This variant is absent from gnomAD v2.1.1 and v3.1.2 controls (PM2_supporting). The computational predictor REVEL gives a score of 0.939, which is above the thresholds predicting a damaging impact on BMPR2 function (PP3). A different change affecting the same amino acid (c.1039T>C p.(Cys347Arg); PMID:26387786) has been reported as likely pathogenic (PM5_supporting). Cytoplasmatic retention assay demonstrates impaired signaling with subcellular localization in HeLa cells showing retainment in endoplasmatic reticulum, not significantly different to empty plasmid. However, this analysis lacks validation controls (PMID:12045205; PS3_supporting). This variant has been reported in 5 probands meeting pulmonary arterial hypertension criteria (PS4 ; PMIDs 10973254; 26645265; 29631995; 31727138). In summary, this 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: PM2_supporting, PS4, PP3, PM5_supporting, PS3_supporting (VCEP specifications version 1.1, 1/18/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA278077/MONDO:0015924/125

• Frequency: Genomes: not found (cov: 32)
• Consequence: BMPR2 NM_001204.7 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4 O:1
• Conservation: PhyloP100: 9.93
• Publications: 12 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

Specifications for BMPR2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001204.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMPR2	NM_001204.7	MANE Select	c.1040G>A	p.Cys347Tyr	missense	Exon 8 of 13	NP_001195.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMPR2	ENST00000374580.10	TSL:1 MANE Select	c.1040G>A	p.Cys347Tyr	missense	Exon 8 of 13	ENSP00000363708.4	Q13873-1
	BMPR2	ENST00000374574.2	TSL:2	c.1040G>A	p.Cys347Tyr	missense	Exon 8 of 12	ENSP00000363702.2	Q13873-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	Pulmonary hypertension, primary, 1 (2)
1	-	-	Pulmonary arterial hypertension (1)
1	-	-	Pulmonary venoocclusive disease 1;C4552070:Pulmonary hypertension, primary, 1 (1)
-	-	-	Pulmonary arterial hypertension;C5679820:Idiopathic and/or familial pulmonary arterial hypertension (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Benign	2.0	M
PhyloP100		9.9
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-8.7	D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.89		Gain of phosphorylation at C347 (P = 0.0412)
MVP		0.99
MPC		1.4
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.98
gMVP		0.92
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs137852744; hg19: chr2-203395589;