rs201067849

Positions:

chr2-202530868-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. BS1PS3_Supporting

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:1B:4

Conservation

PhyloP100: 9.93

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.

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/exons	MANE	Protein	UniProt
BMPR2	NM_001204.7 linkuse as main transcript	c.1042G>A	p.Val348Ile	missense_variant	8/13	ENST00000374580.10	NP_001195.2	Q13873-1
BMPR2	XM_011511687.2 linkuse as main transcript	c.1042G>A	p.Val348Ile	missense_variant	8/13		XP_011509989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BMPR2	ENST00000374580.10 linkuse as main transcript	c.1042G>A	p.Val348Ile	missense_variant	8/13	1	NM_001204.7	ENSP00000363708.4		Q13873-1
BMPR2	ENST00000374574.2 linkuse as main transcript	c.1042G>A	p.Val348Ile	missense_variant	8/12	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

GnomAD3 exomes

AF:

0.000537

AC:

135

AN:

251454

Hom.:

AF XY:

0.000522

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:

0.00734

Gnomad SAS exome

AF:

0.00

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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00363

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.000236

AC:

AN:

152278

Hom.:

Cov.:

AF XY:

0.000295

AC XY:

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00675

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000160

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:1Benign:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Pulmonary hypertension, primary, 1

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Uncertain significance, no assertion criteria provided	literature only	Rare Disease Genomics Group, St George's University of London	-	- -

Pulmonary arterial hypertension

Benign:2

Likely benign, reviewed by expert panel	curation	Clingen Pulmonary Hypertension Variant Curation Expert Panel, ClinGen	May 03, 2024	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). -
Benign, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Nov 05, 2023	- -

Genetic non-acquired premature ovarian failure

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

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

Oct 01, 2019

- -

Tooth agenesis, selective, 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Department of Prosthodontics, Peking University School and Hospital of Stomatology

- -

Primary pulmonary hypertension

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 03, 2023

- -

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

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;.

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

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