rs201781338

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BS3_SupportingBS1BS4

This summary comes from the ClinGen Evidence Repository: The c.2618G>A variant (NM_001204.7) in BMPR2 is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 873 (p.Arg873Gln). This variant has been reported not to segregate with pulmonary arterial hypertension in one affected family member from one family (BS4; Internal lab contributor). The highest population minor allele frequency in gnomAD v2.2.1 controls is 0.001595 in Other East Asian population, which is higher than the ClinGen Pulmonary Hypertension VCEP threshold (≥0.001) for BS1, and therefore meets this criterion (BS1). In vitro reporter system assay in mouse embryonic endothelial cells showed that the c.2618 G>A variant activate BRE-Luc (specific reporter gene for Smad1/5 activation) in response to BMP4 treatment in a similar way as the wild-type BMPR2 reporter gene. However the impairment of another function through an alternative signaling pathway of BMPRII could not be excluded (PMID 25429696)(BS3_Supporting). In summary, this variant meets the criteria to be classified as benign for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP (specification version 1.1, 1/18/2024): BS4, BS1, BS3_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA2061553/MONDO:0015924/125

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000054 ( 0 hom. )

Consequence

BMPR2
NM_001204.7 missense

Scores

Clinical Significance

Benign reviewed by expert panel P:1U:1B:2

Conservation

PhyloP100: 9.56

Publications

9 publications found

Variant links:

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

BMPR2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BS1

For more information check the summary or visit ClinGen Evidence Repository.

BS3

For more information check the summary or visit ClinGen Evidence Repository.

BS4

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 link	c.2618G>A	p.Arg873Gln	missense_variant	Exon 12 of 13	ENST00000374580.10	NP_001195.2
BMPR2	XM_011511687.2 link	c.2618G>A	p.Arg873Gln	missense_variant	Exon 12 of 13		XP_011509989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMPR2	ENST00000374580.10 link	c.2618G>A	p.Arg873Gln	missense_variant	Exon 12 of 13	1	NM_001204.7	ENSP00000363708.4
BMPR2	ENST00000374574.2 link	c.1586+3395G>A		intron_variant	Intron 11 of 11	2		ENSP00000363702.2

Frequencies

GnomAD3 genomes

AF:

0.0000788

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000115

AC:

AN:

251462

AF XY:

0.0000883

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00136

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000540

AC:

AN:

1461872

Hom.:

Cov.:

AF XY:

0.0000660

AC XY:

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.000554

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86238

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000432

AC:

AN:

1112012

Other (OTH)

AF:

0.0000497

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152314

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41576

American (AMR)

AF:

0.00

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000579

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000487

Hom.:

Bravo

AF:

0.0000718

ExAC

AF:

0.000115

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Uncertain:1Benign:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Genetic non-acquired premature ovarian failure

Pathogenic:1

Oct 01, 2019

Center for Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong University

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Pulmonary hypertension, primary, 1

Uncertain:1

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

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Pulmonary arterial hypertension

Benign:1

May 03, 2024

Clingen Pulmonary Hypertension Variant Curation Expert Panel, ClinGen

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

The c.2618G>A variant (NM_001204.7) in BMPR2 is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 873 (p.Arg873Gln). This variant has been reported not to segregate with pulmonary arterial hypertension in one affected family member from one family (BS4; Internal lab contributor). The highest population minor allele frequency in gnomAD v2.2.1 controls is 0.001595 in Other East Asian population, which is higher than the ClinGen Pulmonary Hypertension VCEP threshold (>=0.001) for BS1, and therefore meets this criterion (BS1). In vitro reporter system assay in mouse embryonic endothelial cells showed that the c.2618 G>A variant activate BRE-Luc (specific reporter gene for Smad1/5 activation) in response to BMP4 treatment in a similar way as the wild-type BMPR2 reporter gene. However the impairment of another function through an alternative signaling pathway of BMPRII could not be excluded (PMID 25429696)(BS3_Supporting). In summary, this variant meets the criteria to be classified as benign for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP (specification version 1.1, 1/18/2024): BS4, BS1, BS3_Supporting. -

Primary pulmonary hypertension

Benign:1

Aug 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.42

Eigen

Uncertain

0.59

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

M_CAP

Uncertain

0.095

MetaRNN

Uncertain

0.47

MetaSVM

Uncertain

0.35

MutationAssessor

Uncertain

2.0

PhyloP100

9.6

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-0.86

REVEL

Uncertain

0.55

Sift

Benign

0.13

Sift4G

Uncertain

0.020

Polyphen

0.97

Vest4

0.93

MVP

0.98

MPC

0.70

ClinPred

0.22

GERP RS

6.2

Varity_R

0.32

gMVP

0.40

Mutation Taster

=7/93

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over