rs1085307167

Variant names:

• chr2-202464857-A-G
• rs1085307167
• NM_001204.7:c.125A>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PP3 PM2_Supporting

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 met). The variant is absent from gnomAD v2.1.1 (controls) and v4.1 (PM2_supporting met). The REVEL prediction algorithm score is 0.78, which is above the threshold of 0.75 for pathogenicity (PP3_supporting 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 assessed). Neither segregation or maternity/paternity data are available (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, PP3_supporting (VCEP specification version 1.1.0, 1/18/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA350399166/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: 5.78

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 Uncertain_significance. Variant got 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.
• PP3: 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.125A>G	p.Gln42Arg	missense_variant	Exon 2 of 13	ENST00000374580.10	NP_001195.2
BMPR2	XM_011511687.2	c.125A>G	p.Gln42Arg	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.125A>G	p.Gln42Arg	missense_variant	Exon 2 of 13	1	NM_001204.7	ENSP00000363708.4
BMPR2	ENST00000374574.2	c.125A>G	p.Gln42Arg	missense_variant	Exon 2 of 12	2		ENSP00000363702.2
BMPR2	ENST00000479069.1	n.32A>G		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 met). The variant is absent from gnomAD v2.1.1 (controls) and v4.1 (PM2_supporting met). The REVEL prediction algorithm score is 0.78, which is above the threshold of 0.75 for pathogenicity (PP3_supporting 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 assessed). Neither segregation or maternity/paternity data are available (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, PP3_supporting (VCEP specification version 1.1.0, 1/18/2024). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	D;.;.
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.87	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.9	L;L;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.5	N;N;.
REVEL	Pathogenic	0.79
Sift	Benign	0.15	T;T;.
Sift4G	Benign	0.096	T;T;.
Polyphen		0.55	P;.;.
Vest4		0.67
MutPred		0.78		Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);.;
MVP		0.99
MPC		0.36
ClinPred		0.85	D
GERP RS		5.5
Varity_R		0.44
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs1085307167; hg19: chr2-203329580;