NM_001204.7:c.1171G>A

Variant names:

• chr2-202532627-G-A
• rs1085307308
• NM_001204.7:c.1171G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PS3 PM1 PP3 PM2_Supporting PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The BMPR2 c.1171G>A variant is a missense variant predicted to cause substitution of alanine to threonine at amino acid position 391 (p.(Ala391Thr)). The variant was absent in gnomAD v.4.1.0, so PM2_supporting is met (but not BA1, BS1 nor BS2). Computational predictor REVEL score is 0.86, which is ≥0.75, and AlphaMissense = 0.9729, so PP3 is met and BP4 is not met. This variant is located in the kinase domain (aa 203-504), hence PM1 is met. It does not affect known critical or non-critical amino acids. The variant has been reported in at least two presumably unrelated individuals with IPAH from French (PMID:18356561) and Spanish cohorts (PMID:33007923). Another individual with IPAH was reported in Machado et al. (2009) (PMID:19555857) but it was not clear whether it referred to the same individual as in PMID:18356561, and another report of the French cohort (PMID:25429696) likely referred to the same individual as in PMID:18356561. Hence, PS4_supporting was met as the variant was found in >1 PAH patient. PP1, PS2, PM6 were not met due to the absence of co-segregation data. Experimental evidence demonstraed abolished BMPR2-SMAD signaling via a BRE2-Luc vector luciferase assay in murine embryonic endothelial cells that included appropriate controls and replicates (PS3 met). A different missense variant affecting the same amino acid, c.1172C>A p.(Ala391Asp), was reported in an IPAH individual (PMID:31727138) but was scored as VUS (PM1, PM2_supporting, PM5_supporting, PP3) thus, PM5 was not met. In summary, this variant meets the criteria to be classified as a likely pathogenic for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PS3, PS4_supporting, PM1, PM2_supporting, PP3 (VCEP specification version 1.1.0, 1/18/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA350341771/MONDO:0015924/125

• Frequency: Genomes: not found (cov: 31)
• Consequence: BMPR2 NM_001204.7 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 9.64
• Publications: 1 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 9 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.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: 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.1171G>A	p.Ala391Thr	missense	Exon 9 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.1171G>A	p.Ala391Thr	missense	Exon 9 of 13	ENSP00000363708.4	Q13873-1
	BMPR2	ENST00000374574.2	TSL:2	c.1171G>A	p.Ala391Thr	missense	Exon 9 of 12	ENSP00000363702.2	Q13873-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	Pulmonary arterial hypertension (1)
1	-	-	Pulmonary hypertension, primary, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Benign	1.4	L
PhyloP100		9.6
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.86
Sift	Benign	0.088	T
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.77
MutPred		0.81		Gain of glycosylation at A391 (P = 0.0429)
MVP		0.98
MPC		1.1
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.64
gMVP		0.83
Mutation Taster		=6/94	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: rs1085307308; hg19: chr2-203397350;