rs876657748

Variant names:

• chr2-202520135-T-C
• rs876657748
• NM_001204.7:c.901T>C

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PS3 PS4 PM6 PM1 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.901T>C variant (NM_001204.7) in BMPR2 is a missense variant predicted to cause substitution of serine by proline at amino acid 301 (p.Ser301Pro). The variant is absent from gnomAD v2.1.1 and v3.1.2 controls (PM2_supporting).The variant has been identified in 5 probands, meeting the PH VCEP threshold for PS4 (>4 pro bands; PMIDs 16429395, 18356561, 25917481, 29743074, and PH VCEP internal lab contributors). The variant has been identified as a de novo occurrence in one individual with pulmonary arterial hypertension and unconfirmed parental relationships (PM6; PMID 29743074). Immunostaining in Hela cells transfected with a FLAG-tagged c.901C>T BMPR2 expression construct demonstrated impaired subcellular trafficking of BMPRII (PMID:25688877) and Western-blot analysis of pulmonary artery smooth muscle cells isolated from a patient with the c.901C>T variant showed no BMP4-induced phosphorylation of Smad1/5/8 (PMID:19324947), indicating an effect on protein function (PS3). This variant resides in a conserved kinase domain (amino acids 203 – 504) but is not defined as a critical residue by the ClinGen PH VCEP (PM1_moderate). In summary, this variant meets the criteria to be classified as pathogenic for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP (specification version 1.0): PS4, PM6, PM2_Supporting, PS3, PM1_moderate). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10576586/MONDO:0015924/125

• Frequency: Genomes: not found (cov: 32)
• Consequence: BMPR2 NM_001204.7 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:2 U:1
• Conservation: PhyloP100: 4.54
• Publications: 7 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: Pathogenic. The variant received 13 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.
• PM6: 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.901T>C	p.Ser301Pro	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.901T>C	p.Ser301Pro	missense	Exon 7 of 13	ENSP00000363708.4	Q13873-1
	BMPR2	ENST00000374574.2	TSL:2	c.901T>C	p.Ser301Pro	missense	Exon 7 of 12	ENSP00000363702.2	Q13873-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	Idiopathic and/or familial pulmonary arterial hypertension (1)
1	-	-	Pulmonary arterial hypertension (1)
-	1	-	Pulmonary hypertension, primary, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	-0.066
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.020	T
MetaRNN	Pathogenic	0.82	D
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.92	L
PhyloP100		4.5
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.45
Sift	Benign	0.086	T
Sift4G	Benign	0.080	T
Polyphen		0.046	B
Vest4		0.81
MutPred		0.89		Gain of catalytic residue at S301 (P = 0.0047)
MVP		0.95
MPC		0.48
ClinPred		0.64	D
GERP RS		5.0
Varity_R		0.88
gMVP		0.92
Mutation Taster		=11/89	disease causing

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: rs876657748; hg19: chr2-203384858;