rs201067849

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PS3_SupportingBS1

This summary comes from the ClinGen Evidence Repository: The NM_001204.7(BMPR2) c.1042G>A variant is a missense variant predicted to cause a valine to isoleucine substitution at amino acid 348 (p.Val348Ile). The highest population minor allele frequency in gnomAD v2.1.1 controls is 0.88% (62/7044) alleles in the “Other” East Asian population, which is higher than the ClinGen Pulmonary Hypertension VCEP threshold >0.1% for BS1, and therefore meets this criterion (BS1). PP3 was not met. The computational predictor REVEL gives a score of 0.744 which is below the threshold of >0.75 for pathogenicity. Densitometry analysis indicated a modest reduction in p-SMAD levels but this was not consolidated by additional experimental analysis (PS3_supporting). In summary the variant meets the criteria to be classified as likely benign for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: BS1, PS3_supporting (VCEP specification version 1.1, 1/18/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA2061283/MONDO:0015924/125

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

BMPR2
NM_001204.7 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel P:2U:2B:4

Conservation

PhyloP100: 9.93

Publications

11 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: Likely_benign. The variant received -3 ACMG points.

PS3

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

BS1

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.1042G>A	p.Val348Ile	missense_variant	Exon 8 of 13	ENST00000374580.10	NP_001195.2	Q13873-1
BMPR2	XM_011511687.2 link	c.1042G>A	p.Val348Ile	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 link	c.1042G>A	p.Val348Ile	missense_variant	Exon 8 of 13	1	NM_001204.7	ENSP00000363708.4		Q13873-1
BMPR2	ENST00000374574.2 link	c.1042G>A	p.Val348Ile	missense_variant	Exon 8 of 12	2		ENSP00000363702.2		Q13873-2

Frequencies

GnomAD3 genomes

AF:

0.000243

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00693

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000537

AC:

135

AN:

251454

AF XY:

0.000522

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00734

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000109

AC:

159

AN:

1461786

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

727198

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00363

AC:

144

AN:

39694

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000630

AC:

AN:

1111934

Other (OTH)

AF:

0.000116

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

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:

0.000236

AC:

AN:

152278

Hom.:

Cov.:

AF XY:

0.000295

AC XY:

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41550

American (AMR)

AF:

0.00

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00675

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68030

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

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:

0.000113

Hom.:

Bravo

AF:

0.000242

ExAC

AF:

0.000453

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Pathogenic:2Uncertain:2Benign:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Pulmonary arterial hypertension

Uncertain:1Benign:2

May 03, 2024

Clingen Pulmonary Hypertension Variant Curation Expert Panel, ClinGen

Significance:Likely benign

Review Status:reviewed by expert panel

Collection Method:curation

The NM_001204.7(BMPR2) c.1042G>A variant is a missense variant predicted to cause a valine to isoleucine substitution at amino acid 348 (p.Val348Ile). The highest population minor allele frequency in gnomAD v2.1.1 controls is 0.88% (62/7044) alleles in the “Other” East Asian population, which is higher than the ClinGen Pulmonary Hypertension VCEP threshold >0.1% for BS1, and therefore meets this criterion (BS1). PP3 was not met. The computational predictor REVEL gives a score of 0.744 which is below the threshold of >0.75 for pathogenicity. Densitometry analysis indicated a modest reduction in p-SMAD levels but this was not consolidated by additional experimental analysis (PS3_supporting). In summary the variant meets the criteria to be classified as likely benign for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: BS1, PS3_supporting (VCEP specification version 1.1, 1/18/2024). -

Nov 05, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 10, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Pulmonary hypertension, primary, 1

Uncertain:1Benign:1

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

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

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

- -

Tooth agenesis, selective, 1

Pathogenic:1

Department of Prosthodontics, Peking University School and Hospital of Stomatology

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Primary pulmonary hypertension

Benign:1

Sep 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

T;.;.

Eigen

Uncertain

0.64

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.83

T;D;D

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.017

T;T;T

MetaSVM

Pathogenic

0.84

MutationAssessor

Benign

1.7

L;L;.

PhyloP100

9.9

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-0.45

N;N;.

REVEL

Pathogenic

0.74

Sift

Uncertain

0.023

D;T;.

Sift4G

Benign

0.26

T;T;.

Polyphen

0.71

P;.;.

Vest4

0.77

MVP

0.98

MPC

0.90

ClinPred

0.14

GERP RS

5.7

Varity_R

0.36

gMVP

0.48

Mutation Taster

=26/74

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