NM_001204.7:c.908G>A

Variant names:

• chr2-202520142-G-A
• rs200948870
• NM_001204.7:c.908G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PS3 PM1

This summary comes from the ClinGen Evidence Repository: The BMPR2 c.908G>A variant is a missense variant in exon 7 predicted to result in substitution of arginine to histidine at amino acid position 303 (p. Arg303His). The highest population minor allele frequency in gnomAD v2.1.1 (controls) is 0.00043 (1/2334 alleles) in subpopulation “remaining individuals” which exceeds the ClinGen PH VCEP threshold (<0.01%) for PM2 (PM2 not met). Neither BS1 (≥0.1%) nor BA1 (1%) met. The computational predictor REVEL gives a score of 0.497 indicating neither PP3 (≥0.75) nor BP4 (≤0.25) met. SpliceAI algorithm predicts no deleterious effect on acceptor or donor splice site. The variant is located in the kinase domain (PM1 met). Genetic evidence showed the presence of the variant in only one IPAH patient (PMID:16429395) (PS4 not met). Immunofluorescence staining of Hela cells transfected with an R303H mutant construct showed mislocalization of BMPR2 protein to the endoplasmic reticulum (PMID:25688877) and included positive and negative controls (PS3 met). 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: PS3, PM1 (VCEP specification version 1.1, 1/18/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA2061247/MONDO:0015924/125

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: BMPR2 NM_001204.7 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 U:4
• Conservation: PhyloP100: 7.47
• Publications: 3 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 6 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: 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.908G>A	p.Arg303His	missense	Exon 7 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.908G>A	p.Arg303His	missense	Exon 7 of 13	ENSP00000363708.4	Q13873-1
	BMPR2	ENST00000374574.2	TSL:2	c.908G>A	p.Arg303His	missense	Exon 7 of 12	ENSP00000363702.2	Q13873-2

Frequencies

GnomAD3 genomes AF: 0.0000531 AC: 8 AN: 150672 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000489

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000665

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000589

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 251372 AF XY: 0.0000294

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000397 AC: 58 AN: 1461728 Hom.: 0 Cov.: 31 AF XY: 0.0000385 AC XY: 28 AN XY: 727158

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.0000894 AC: 4 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39680

South Asian (SAS) AF: 0.0000928 AC: 8 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53354

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.0000351 AC: 39 AN: 1111960

Other (OTH) AF: 0.0000331 AC: 2 AN: 60386

GnomAD4 genome AF: 0.0000531 AC: 8 AN: 150790 Hom.: 0 Cov.: 32 AF XY: 0.0000816 AC XY: 6 AN XY: 73496

African (AFR) AF: 0.0000488 AC: 2 AN: 41020

American (AMR) AF: 0.0000665 AC: 1 AN: 15048

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5138

South Asian (SAS) AF: 0.000209 AC: 1 AN: 4794

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10144

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000589 AC: 4 AN: 67882

Other (OTH) AF: 0.00 AC: 0 AN: 2096

Alfa AF: 0.0000638 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000330 AC: 4

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
1	1	-	Pulmonary hypertension, primary, 1 (2)
1	-	-	Pulmonary arterial hypertension (1)
-	1	-	Pulmonary venoocclusive disease 1;C4552070:Pulmonary hypertension, primary, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.41	T
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	1.5	L
PhyloP100		7.5
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.50
Sift	Benign	0.10	T
Sift4G	Benign	0.15	T
Polyphen		1.0	D
Vest4		0.93
MVP		0.91
MPC		1.1
ClinPred		0.37	T
GERP RS		5.0
Varity_R		0.47
gMVP		0.74
Mutation Taster		=20/80	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs200948870; hg19: chr2-203384865; COSMIC: COSV65813036; COSMIC: COSV65813036;