NM_001204.7:c.-669G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The BMPR2 c.-669G>A variant is a 5’UTR variant with contradictory evidence for a functional promoter effect (PMID:19223935 and PMID:30336198). Both reports included luciferase assays comparing transcriptional activity of cells expressing wild-type or variant promoter constructs. PMID:19223935 reported a negative effect on BMPR2 expression but the assay used a short 300 bp promoter fragment and no known pathogenic or benign variant controls. PMID:30336198 reported no effect on BMPR2 expression using longer 1520 bp promoter fragments and included nine different PAH associated variants. Based on the latter report, PS3 was not applied. PMID:26387786 reported three PAH probands with the c.-669G>A variant. However, the variant has also been identified in numerous individuals from control populations. In gnomAD v2.1.1 controls (11/2022), the Estonian population had an AF of 2.65% (105/3956 alleles, including 2 homozygotes) which is higher than the ClinGen Pulmonary Hypertension VCEP threshold of >1% for BA1, and therefore meets this stand-alone criterion (BA1). In summary, the variant meets the criteria to be classified as benign for pulmonary arterial hypertension based on ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: BA1 (VCEP specification version 1.1, 1/18/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10613567/MONDO:0015924/125

Frequency

Genomes: 𝑓 0.0061 ( 11 hom., cov: 31)

Exomes 𝑓: 0.0082 ( 13 hom. )

Consequence

BMPR2
NM_001204.7 5_prime_UTR

Scores

Clinical Significance

Benign reviewed by expert panel B:8

Conservation

PhyloP100: 0.918

Publications

5 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:

ENSG00000273456 (HGNC:):

ENSG00000273456 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BA1

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.-669G>A		5_prime_UTR_variant	Exon 1 of 13	ENST00000374580.10	NP_001195.2	Q13873-1
BMPR2	XM_011511687.2 link	c.-669G>A		5_prime_UTR_variant	Exon 1 of 13		XP_011509989.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
BMPR2	ENST00000374580.10 link	c.-669G>A	5_prime_UTR_variant	Exon 1 of 13	1	NM_001204.7	ENSP00000363708.4	Q13873-1
ENSG00000273456	ENST00000724884.1 link	n.139C>T	non_coding_transcript_exon_variant	Exon 1 of 2
ENSG00000273456	ENST00000724885.1 link	n.-68C>T	upstream_gene_variant

Frequencies

GnomAD3 genomes

AF:

0.00609

AC:

922

AN:

151324

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00119

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00171

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00199

Gnomad SAS

AF:

0.00233

Gnomad FIN

AF:

0.0185

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00914

Gnomad OTH

AF:

0.00291

GnomAD4 exome

AF:

0.00818

AC:

2044

AN:

249938

Hom.:

AF XY:

0.00810

AC XY:

1030

AN XY:

127140

show subpopulations

African (AFR)

AF:

0.00125

AC:

AN:

7176

American (AMR)

AF:

0.00103

AC:

AN:

7756

Ashkenazi Jewish (ASJ)

AF:

0.00184

AC:

AN:

9258

East Asian (EAS)

AF:

0.00200

AC:

AN:

22970

South Asian (SAS)

AF:

0.00210

AC:

AN:

2854

European-Finnish (FIN)

AF:

0.0214

AC:

445

AN:

20832

Middle Eastern (MID)

AF:

0.00383

AC:

AN:

1304

European-Non Finnish (NFE)

AF:

0.00871

AC:

1404

AN:

161246

Other (OTH)

AF:

0.00629

AC:

104

AN:

16542

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

103

206

310

413

516

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00608

AC:

921

AN:

151442

Hom.:

Cov.:

AF XY:

0.00647

AC XY:

478

AN XY:

73926

show subpopulations

African (AFR)

AF:

0.00118

AC:

AN:

41358

American (AMR)

AF:

0.00171

AC:

AN:

15194

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3466

East Asian (EAS)

AF:

0.00199

AC:

AN:

5022

South Asian (SAS)

AF:

0.00212

AC:

AN:

4722

European-Finnish (FIN)

AF:

0.0185

AC:

195

AN:

10552

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00914

AC:

620

AN:

67846

Other (OTH)

AF:

0.00288

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

144

192

240

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00835

Hom.:

Bravo

AF:

0.00432

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:2

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BMPR2: BS1 -

Nov 14, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Primary pulmonary hypertension

Benign:2

Feb 07, 2024

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:literature only

The NM_001204.7(BMPR2):c.-669G>A variant has an allele frequency of >2% in the European (Finnish) population and has been observed in the homozygous state (n=24) in the gnomAD database (v.4.0.0). Therefore, this variant meets our criteria to be classified as benign, based on allele frequency data. -

Nov 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Pulmonary arterial hypertension

Benign:1

May 01, 2024

Clingen Pulmonary Hypertension Variant Curation Expert Panel, ClinGen

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

The BMPR2 c.-669G>A variant is a 5’UTR variant with contradictory evidence for a functional promoter effect (PMID: 19223935 and PMID: 30336198). Both reports included luciferase assays comparing transcriptional activity of cells expressing wild-type or variant promoter constructs. PMID: 19223935 reported a negative effect on BMPR2 expression but the assay used a short 300 bp promoter fragment and no known pathogenic or benign variant controls. PMID: 30336198 reported no effect on BMPR2 expression using longer 1520 bp promoter fragments and included nine different PAH associated variants. Based on the latter report, PS3 was not applied. PMID: 26387786 reported three PAH probands with the c.-669G>A variant. However, the variant has also been identified in numerous individuals from control populations. In gnomAD v2.1.1 controls (11/2022), the Estonian population had an AF of 2.65% (105/3956 alleles, including 2 homozygotes) which is higher than the ClinGen Pulmonary Hypertension VCEP threshold of >1% for BA1, and therefore meets this stand-alone criterion (BA1). In summary, the variant meets the criteria to be classified as benign for pulmonary arterial hypertension based on ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: BA1 (VCEP specification version 1.1, 1/18/2024). -

not specified

Benign:1

May 04, 2022

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Pulmonary venoocclusive disease 1;C4552070:Pulmonary hypertension, primary, 1

Benign:1

Apr 14, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Pulmonary hypertension, primary, 1

Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

5.9

(source)

DANN

Benign

0.74

PhyloP100

0.92

PromoterAI

-0.049

Neutral

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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NM_001204.7:c.-669G>A

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