rs137852754

Positions:

chr2-202514903-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS3

This summary comes from the ClinGen Evidence Repository: The NM_0001204.7(BMPR2) c.545G>A variant is a missense variant predicted to cause substitution of glycine by aspartic acid at amino acid 182 (p.Gly182Asp). The highest subpopulation minor allele frequency in gnomAD v2.1.1 (controls) is 0.0003507 in the European (non-Finnish) population, which is higher than the ClinGen PH VCEP threshold (<0.01%) for PM2 but lower than the threshold (>0.1%) for BS1. Therefore, this variant does not meet either of these population criteria. The REVEL computational prediction analysis tool produced a score of 0.8069, which is above the threshold (>0.75) for pathogenicity (PP3). Luciferase assay data indicated that variant transcriptional activity was comparable to wild-type, indicating no deleterious effect (BS3; PMID:18321866). The PH Expert Panel reviewed the conflicting evidence (PP3) and felt it did not override the Likely Benign classification in this case. In summary, this 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: BS3, PP3. (VCEP specifications version 1.1, 1/18/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA119936/MONDO:0015924/125

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00026 ( 0 hom. )

Consequence

BMPR2
NM_001204.7 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel P:1U:5B:2

Conservation

PhyloP100: 9.32

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP3

BS3

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BMPR2	NM_001204.7 linkuse as main transcript	c.545G>A	p.Gly182Asp	missense_variant	5/13	ENST00000374580.10
BMPR2	XM_011511687.2 linkuse as main transcript	c.545G>A	p.Gly182Asp	missense_variant	5/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMPR2	ENST00000374580.10 linkuse as main transcript	c.545G>A	p.Gly182Asp	missense_variant	5/13	1	NM_001204.7	P1	Q13873-1
BMPR2	ENST00000374574.2 linkuse as main transcript	c.545G>A	p.Gly182Asp	missense_variant	5/12	2			Q13873-2

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.000958

GnomAD3 exomes

AF:

0.000139

AC:

AN:

251456

Hom.:

AF XY:

0.000147

AC XY:

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000308

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000263

AC:

385

AN:

1461726

Hom.:

Cov.:

AF XY:

0.000246

AC XY:

179

AN XY:

727168

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000334

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.000151

AC:

AN:

152072

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74274

show subpopulations

Gnomad4 AFR

AF:

0.0000966

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000250

Gnomad4 OTH

AF:

0.000958

Alfa

AF:

0.000318

Hom.:

Bravo

AF:

0.000159

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000140

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000415

ClinVar

Significance: Likely benign

Submissions summary: Pathogenic:1Uncertain:5Benign:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 23, 2018	The BMPR2 c.545G>A; p.Gly182Asp variant (rs137852754) has been previously identified in a patient diagnosed with fenfluramine-associated primary pulmonary hypertension (PAH) after taking the drug for 2 months (Humbert 2002). It is reported in ClinVar (Variation ID: 8813) and is observed in the non-Finnish European population at an overall frequency of 0.03% (38/126718 alleles) in the Genome Aggregation Database. The glycine at codon 182 is highly conserved but computational algorithms (SIFT: tolerated, PolyPhen2: damaging) predict conflicting effects of this variant on protein structure/function. Functional studies have suggested that the variant protein induces a transcriptional response following BMP4 stimulation in a manner indistinguishable from wild type BMPR2, although statistical analyses supporting this conclusion were not performed (Nasim 2008). Due to incomplete and conflicting information, the clinical significance of this variant cannot be determined with certainty. References: Humbert et al. BMPR2 germline mutations in pulmonary hypertension associated with fenfluramine derivatives. Eur Respir J. 2002; 20(3): 518-523. Nasim et al. Stoichiometric imbalance in the receptor complex contributes to dysfunctional BMPR-II mediated signalling in pulmonary arterial hypertension. Hum Mol Genet. 2008; 17(11): 1683-1694. -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BMPR2 p.Gly182Asp variant was identified in one individual with fenfluramine-associated pulmonary hypertension (Humbert_2002_PMID:12358323). Functional analysis revealed no difference in BMPR2 protein activity with the p.Gly182Asp variant compared to wild type (Nasim_ 2008_PMID:18321866). The variant was identified in dbSNP (ID: rs137852754), ClinVar (classified as uncertain significance by ARUP Laboratories and CHLA Center for Personalized Medicine), and LOVD 3.0 (variant effect not shared). The variant was identified in control databases in 39 of 282854 chromosomes at a frequency of 0.0001379 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the European (non-Finnish) population in 39 of 129172 chromosomes (freq: 0.000302), but was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other, or South Asian populations. The p.Gly182 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	BMPR2: PM2:Supporting, PP3 -

Pulmonary hypertension, primary, fenfluramine-associated

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2002

- -

Micrognathia;C0036572:Seizure;C0221263:Cafe-au-lait spot;C0221354:Frontal bossing;C0239676:High forehead;C0338656:Cognitive impairment;C1857790:Thoracic scoliosis;C4022745:Abnormal basal ganglia MRI signal intensity;C4520981:Abnormal basal ganglia morphology

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Personalized Medicine, Children's Hospital Los Angeles

- -

Pulmonary hypertension, primary, 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Aug 28, 2019

A heterozygous missense variant was identified, NM_001204.6(BMPR2):c.545G>A in exon 5 of 13 of the BMPR2 gene. This substitution is predicted to create a moderate amino acid change from glycine to aspartic acid at position 182 of the protein, NP_001195.2(BMPR2):p.(Gly182Asp). The glycine at this position has very high conservation (100 vertebrates, UCSC), but is not situated in a known functional domain. In silico software predicts this variant to be pathogenic (PolyPhen, SIFT, CADD, MutationTaster). The variant is present in the gnomAD population database at a frequency of 0.014% (39 heterozygotes; 0 homozygotes). The variant has been previously reported in a patient with pulmonary hypertension and also described as a VUS (ClinVar, Humbert, M. et al. (2002)). In addition, functional studies of the variant showed that transcriptional activities were comparable to wild-type (Nasim, M. et al. (2008)). Based on information available at the time of curation, this variant has been classified as a VARIANT of UNCERTAIN SIGNIFICANCE (VUS). -

Pulmonary arterial hypertension

Benign:1

Likely benign, reviewed by expert panel

curation

Clingen Pulmonary Hypertension Variant Curation Expert Panel, ClinGen

May 03, 2024

The NM_0001204.7(BMPR2) c.545G>A variant is a missense variant predicted to cause substitution of glycine by aspartic acid at amino acid 182 (p.Gly182Asp). The highest subpopulation minor allele frequency in gnomAD v2.1.1 (controls) is 0.0003507 in the European (non-Finnish) population, which is higher than the ClinGen PH VCEP threshold (<0.01%) for PM2 but lower than the threshold (>0.1%) for BS1. Therefore, this variant does not meet either of these population criteria. The REVEL computational prediction analysis tool produced a score of 0.8069, which is above the threshold (>0.75) for pathogenicity (PP3). Luciferase assay data indicated that variant transcriptional activity was comparable to wild-type, indicating no deleterious effect (BS3; PMID: 18321866). The PH Expert Panel reviewed the conflicting evidence (PP3) and felt it did not override the Likely Benign classification in this case. In summary, this 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: BS3, PP3. (VCEP specifications version 1.1, 1/18/2024) -

Primary pulmonary hypertension

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 24, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.38

T;.;.

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D;D

M_CAP

Benign

0.060

MetaRNN

Uncertain

0.66

D;D;D

MetaSVM

Uncertain

0.32

MutationAssessor

Benign

2.0

M;M;.

MutationTaster

Benign

1.0

A;A

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-1.7

N;N;.

REVEL

Pathogenic

0.81

Sift

Benign

0.075

T;T;.

Sift4G

Benign

0.075

T;T;.

Polyphen

1.0

D;.;.

Vest4

0.83

MVP

0.95

MPC

1.2

ClinPred

0.33

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.24

gMVP

0.76

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over