chr2-202532627-G-A

Position:

• chr2-202532627-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 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

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 Likely_pathogenic. Variant got 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BMPR2	NM_001204.7	c.1171G>A	p.Ala391Thr	missense_variant	9/13	ENST00000374580.10	NP_001195.2
BMPR2	XM_011511687.2	c.1171G>A	p.Ala391Thr	missense_variant	9/13		XP_011509989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BMPR2	ENST00000374580.10	c.1171G>A	p.Ala391Thr	missense_variant	9/13	1	NM_001204.7	ENSP00000363708.4
BMPR2	ENST00000374574.2	c.1171G>A	p.Ala391Thr	missense_variant	9/12	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

Likely pathogenic, reviewed by expert panel

curation

Clingen Pulmonary Hypertension Variant Curation Expert Panel, ClinGen

Nov 06, 2024

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). -

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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Computational scores

Source: dbNSFP v4.3

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;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Benign	1.4	L;L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.9	D;D;.
REVEL	Pathogenic	0.86
Sift	Benign	0.088	T;D;.
Sift4G	Uncertain	0.0050	D;D;.
Polyphen		1.0	D;.;.
Vest4		0.77
MutPred		0.81		Gain of glycosylation at A391 (P = 0.0429);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs1085307308; hg19: chr2-203397350;