NM_001204.7:c.1040G>A

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. Variant got 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

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 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMPR2	NM_001204.7	c.1040G>A	p.Cys347Tyr	missense_variant	Exon 8 of 13	ENST00000374580.10	NP_001195.2
BMPR2	XM_011511687.2	c.1040G>A	p.Cys347Tyr	missense_variant	Exon 8 of 13		XP_011509989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMPR2	ENST00000374580.10	c.1040G>A	p.Cys347Tyr	missense_variant	Exon 8 of 13	1	NM_001204.7	ENSP00000363708.4
BMPR2	ENST00000374574.2	c.1040G>A	p.Cys347Tyr	missense_variant	Exon 8 of 12	2		ENSP00000363702.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Pulmonary hypertension, primary, 1 Pathogenic:2

-

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Sep 01, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Pulmonary arterial hypertension Pathogenic:1

May 01, 2024

Clingen Pulmonary Hypertension Variant Curation Expert Panel, ClinGen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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). -

Pulmonary venoocclusive disease 1;C4552070:Pulmonary hypertension, primary, 1 Pathogenic:1

Jun 17, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

-

Wendy Chung Laboratory, Columbia University Medical Center

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

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;D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Benign	2.0	M;M;.
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-8.7	D;D;.
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0010	D;D;.
Polyphen		1.0	D;.;.
Vest4		0.96
MutPred		0.89		Gain of phosphorylation at C347 (P = 0.0412);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

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: rs137852744; hg19: chr2-203395589;