rs1085307168

Variant names:

• chr2-202464872-G-A
• rs1085307168
• NM_001204.7:c.140G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM1

This summary comes from the ClinGen Evidence Repository: The NM_001204.7(BMPR2):c.140G>A (p.Gly47Asp) variant is a missense variant located within exon 2 of BMPR2, predicted to cause substitution of glycine to an aspartic acid. This variant is located within the conserved extracellular domain of the protein but does not affect a known critical residue (PM1_moderate). The variant is absent from gnomAD v2.1.1 (controls) and v4.1 (PM2_supporting). The REVEL prediction algorithm score is 0.55, which is below our threshold of >=0.75 for pathogenicity (PP3_not met) and above our threshold for benignity (BP4 not met). The variant has been reported in an individual with PAH associated with congenital heart disease (PMID:15358693) but not in patients with hereditary or idiopathic PAH (PS4 not met). Alternative alleles at the same nucleotide or amino acid have not been reported (PS1 and PM5 not met). Functional studies have not been reported (PS3, not evaluated). Neither segregation or maternity/paternity studies have not been reported (PS2, PP1, BS4 not evaluated). In summary, this variant meets the criteria to be classified as a variant of unknown significance for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM1_moderate, PM2_supporting (VCEP specification version 1.1.0, 1/18/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA350399236/MONDO:0015924/125

• Frequency: Genomes: not found (cov: 32)
• Consequence: BMPR2 NM_001204.7 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1
• Conservation: PhyloP100: 5.20
• Publications: 1 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: 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	c.140G>A	p.Gly47Asp	missense_variant	Exon 2 of 13	ENST00000374580.10	NP_001195.2
BMPR2	XM_011511687.2	c.140G>A	p.Gly47Asp	missense_variant	Exon 2 of 13		XP_011509989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMPR2	ENST00000374580.10	c.140G>A	p.Gly47Asp	missense_variant	Exon 2 of 13	1	NM_001204.7	ENSP00000363708.4
BMPR2	ENST00000374574.2	c.140G>A	p.Gly47Asp	missense_variant	Exon 2 of 12	2		ENSP00000363702.2
BMPR2	ENST00000479069.1	n.47G>A		non_coding_transcript_exon_variant	Exon 1 of 3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Pulmonary arterial hypertension associated with congenital heart disease Pathogenic:1

-

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Pulmonary arterial hypertension Uncertain:1

Jan 22, 2025

Clingen Pulmonary Hypertension Variant Curation Expert Panel, ClinGen

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The NM_001204.7(BMPR2):c.140G>A (p.Gly47Asp) variant is a missense variant located within exon 2 of BMPR2, predicted to cause substitution of glycine to an aspartic acid. This variant is located within the conserved extracellular domain of the protein but does not affect a known critical residue (PM1_moderate). The variant is absent from gnomAD v2.1.1 (controls) and v4.1 (PM2_supporting). The REVEL prediction algorithm score is 0.55, which is below our threshold of >=0.75 for pathogenicity (PP3_not met) and above our threshold for benignity (BP4 not met). The variant has been reported in an individual with PAH associated with congenital heart disease (PMID: 15358693) but not in patients with hereditary or idiopathic PAH (PS4 not met). Alternative alleles at the same nucleotide or amino acid have not been reported (PS1 and PM5 not met). Functional studies have not been reported (PS3, not evaluated). Neither segregation or maternity/paternity studies have not been reported (PS2, PP1, BS4 not evaluated). In summary, this variant meets the criteria to be classified as a variant of unknown significance for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM1_moderate, PM2_supporting (VCEP specification version 1.1.0, 1/18/2024). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T;.;.
Eigen	Benign	-0.052
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.82	T;T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.68	D;D;D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Benign	0.46	N;N;.
PhyloP100		5.2
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.47	N;N;.
REVEL	Uncertain	0.55
Sift	Uncertain	0.024	D;T;.
Sift4G	Benign	0.27	T;T;.
Polyphen		0.0070	B;.;.
Vest4		0.31
MutPred		0.78		Loss of catalytic residue at S49 (P = 0.0135);Loss of catalytic residue at S49 (P = 0.0135);.;
MVP		0.96
MPC		0.43
ClinPred		0.74	D
GERP RS		5.5
Varity_R		0.47
gMVP		0.77
Mutation Taster		=30/70	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.33		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.33		Position offset: 47

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

Other links and lift over

dbSNP: rs1085307168; hg19: chr2-203329595;