rs115604088

Positions:

• chr2-202376806-G-A

Variant summary

Our verdict is Benign. Variant got -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
• Clinical Significance: Benign reviewed by expert panel B:8
• Conservation: PhyloP100: 0.918

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BA1: 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	c.-669G>A		5_prime_UTR_variant	1/13	ENST00000374580.10	NP_001195.2
BMPR2	XM_011511687.2	c.-669G>A		5_prime_UTR_variant	1/13		XP_011509989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BMPR2	ENST00000374580	c.-669G>A		5_prime_UTR_variant	1/13	1	NM_001204.7	ENSP00000363708.4

Frequencies

GnomAD3 genomes AF: 0.00609 AC: 922 AN: 151324 Hom.: 11 Cov.: 31

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.: 13 AF XY: 0.00810 AC XY: 1030 AN XY: 127140

Gnomad4 AFR exome AF: 0.00125

Gnomad4 AMR exome AF: 0.00103

Gnomad4 ASJ exome AF: 0.00184

Gnomad4 EAS exome AF: 0.00200

Gnomad4 SAS exome AF: 0.00210

Gnomad4 FIN exome AF: 0.0214

Gnomad4 NFE exome AF: 0.00871

Gnomad4 OTH exome AF: 0.00629

GnomAD4 genome AF: 0.00608 AC: 921 AN: 151442 Hom.: 11 Cov.: 31 AF XY: 0.00647 AC XY: 478 AN XY: 73926

Gnomad4 AFR AF: 0.00118

Gnomad4 AMR AF: 0.00171

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00199

Gnomad4 SAS AF: 0.00212

Gnomad4 FIN AF: 0.0185

Gnomad4 NFE AF: 0.00914

Gnomad4 OTH AF: 0.00288

Alfa AF: 0.0103 Hom.: 3

Bravo AF: 0.00432

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	BMPR2: BS1 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 28, 2023	- -

Primary pulmonary hypertension Benign:2

Benign, no assertion criteria provided	literature only	Rare Disease Genomics Group, St George's University of London	Feb 07, 2024	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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 14, 2023	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Pulmonary arterial hypertension Benign:1

Benign, reviewed by expert panel

curation

Clingen Pulmonary Hypertension Variant Curation Expert Panel, ClinGen

May 01, 2024

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). -

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

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 14, 2022

- -

Pulmonary hypertension, primary, 1 Benign: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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.9
DANN	Benign	0.74

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs115604088; hg19: chr2-203241529;