rs1085307163

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1_StrongPS3PM5_SupportingPM2_SupportingPS4_SupportingPP3

This summary comes from the ClinGen Evidence Repository: The NM_001204.7(BMPR2) c.100T>C variant is a missense variant predicted to cause a cysteine to arginine substitution at amino acid position 34 (p.Cys34Arg). The variant is absent from gnomAD v.2.1.1 and v4.1 (PM2_supporting) and has been reported in two unrelated PAH probands (PMID:29650961) (PS4_supporting). The variant is located within the extracellular ligand-binding domain and p.Cys34 is a critical residue for protein function (PM1_strong). Two additional likely pathogenic variants, c.101G>T (p.Cys34Phe) and c.102T>G (p.Cys34Trp) have been reported at the same residue (PMID:27453251, PMID:30578397) (PM5_supporting). HeLa cells transfected with a BMPR2 p.C34R construct demonstrated that the mutant protein is mislocalized in the cell and does not reach the plasma membrane, with some retention in the ER/Golgi (PMID:25688877) (PS3). In silico prediction (REVEL = 0.939) is consistent with a pathogenic effect for this variant (PP3). In summary, the variant meets the criteria to be classified as pathogenic for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PS3, PS4_supporting, PM1_strong, PM2_supporting, PM5_supporting, PP3 (VCEP specification version v 1.1, 1/18/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA350399040/MONDO:0015924/125

Frequency

Genomes: not found (cov: 32)

Consequence

BMPR2
NM_001204.7 missense

Scores

13
4
2

Clinical Significance

Pathogenic reviewed by expert panel P:3

Conservation

PhyloP100: 6.51
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PS3
For more information check the summary or visit ClinGen Evidence Repository.
PS4
For more information check the summary or visit ClinGen Evidence Repository.
PM1
For more information check the summary or visit ClinGen Evidence Repository.
PM2
For more information check the summary or visit ClinGen Evidence Repository.
PM5
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
BMPR2NM_001204.7 linkc.100T>C p.Cys34Arg missense_variant Exon 2 of 13 ENST00000374580.10 NP_001195.2 Q13873-1
BMPR2XM_011511687.2 linkc.100T>C p.Cys34Arg missense_variant Exon 2 of 13 XP_011509989.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
BMPR2ENST00000374580.10 linkc.100T>C p.Cys34Arg missense_variant Exon 2 of 13 1 NM_001204.7 ENSP00000363708.4 Q13873-1
BMPR2ENST00000374574.2 linkc.100T>C p.Cys34Arg missense_variant Exon 2 of 12 2 ENSP00000363702.2 Q13873-2
BMPR2ENST00000479069.1 linkn.7T>C 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: Pathogenic
Submissions summary: Pathogenic:3
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Pulmonary arterial hypertension Pathogenic:2
Pathogenic, reviewed by expert panelcurationClingen Pulmonary Hypertension Variant Curation Expert Panel, ClinGenSep 20, 2024The NM_001204.7(BMPR2) c.100T>C variant is a missense variant predicted to cause a cysteine to arginine substitution at amino acid position 34 (p.Cys34Arg). The variant is absent from gnomAD v.2.1.1 and v4.1 (PM2_supporting) and has been reported in two unrelated PAH probands (PMID: 29650961) (PS4_supporting). The variant is located within the extracellular ligand-binding domain and p.Cys34 is a critical residue for protein function (PM1_strong). Two additional likely pathogenic variants, c.101G>T (p.Cys34Phe) and c.102T>G (p.Cys34Trp) have been reported at the same residue (PMID: 27453251, PMID: 30578397) (PM5_supporting). HeLa cells transfected with a BMPR2 p.C34R construct demonstrated that the mutant protein is mislocalized in the cell and does not reach the plasma membrane, with some retention in the ER/Golgi (PMID: 25688877) (PS3). In silico prediction (REVEL = 0.939) is consistent with a pathogenic effect for this variant (PP3). In summary, the variant meets the criteria to be classified as pathogenic for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PS3, PS4_supporting, PM1_strong, PM2_supporting, PM5_supporting, PP3 (VCEP specification version v 1.1, 1/18/2024). -
Pathogenic, no assertion criteria providedresearchNIHR Bioresource Rare Diseases, University of Cambridge-- -
Pulmonary hypertension, primary, 1 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyRare Disease Genomics Group, St George's University of London-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.54
D
BayesDel_noAF
Pathogenic
0.54
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.94
D;.;.
Eigen
Pathogenic
0.72
Eigen_PC
Pathogenic
0.71
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.81
T;T;T
M_CAP
Pathogenic
0.82
D
MetaRNN
Pathogenic
0.99
D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Uncertain
2.0
M;M;.
PrimateAI
Uncertain
0.78
T
PROVEAN
Pathogenic
-6.2
D;D;.
REVEL
Pathogenic
0.94
Sift
Pathogenic
0.0
D;D;.
Sift4G
Uncertain
0.020
D;D;.
Polyphen
1.0
D;.;.
Vest4
0.97
MutPred
0.95
Loss of sheet (P = 0.0054);Loss of sheet (P = 0.0054);.;
MVP
1.0
MPC
1.5
ClinPred
1.0
D
GERP RS
5.4
Varity_R
0.98
gMVP
0.89

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.11
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.

Other links and lift over

dbSNP: rs1085307163; hg19: chr2-203329555; API