rs200948870
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM1PP2BS2
The NM_001204.7(BMPR2):c.908G>A(p.Arg303His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000409 in 1,612,518 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000040 ( 0 hom. )
Consequence
BMPR2
NM_001204.7 missense
NM_001204.7 missense
Scores
6
4
9
Clinical Significance
Conservation
PhyloP100: 7.47
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 Likely_benign. Variant got -1 ACMG points.
PM1
?
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_001204.7
PP2
?
Missense variant where missense usually causes diseases, BMPR2
BS2
?
High AC in GnomAd at 8 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BMPR2 | NM_001204.7 | c.908G>A | p.Arg303His | missense_variant | 7/13 | ENST00000374580.10 | |
BMPR2 | XM_011511687.2 | c.908G>A | p.Arg303His | missense_variant | 7/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BMPR2 | ENST00000374580.10 | c.908G>A | p.Arg303His | missense_variant | 7/13 | 1 | NM_001204.7 | P1 | |
BMPR2 | ENST00000374574.2 | c.908G>A | p.Arg303His | missense_variant | 7/12 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000531 AC: 8AN: 150672Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251372Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135874
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GnomAD4 exome AF: 0.0000397 AC: 58AN: 1461728Hom.: 0 Cov.: 31 AF XY: 0.0000385 AC XY: 28AN XY: 727158
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GnomAD4 genome ? AF: 0.0000531 AC: 8AN: 150790Hom.: 0 Cov.: 32 AF XY: 0.0000816 AC XY: 6AN XY: 73496
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ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Pulmonary hypertension, primary, 1 Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Sep 02, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with familial primary pulmonary hypertension 1, with or without HHT (MIM#178600), primary fenfluramine or dexfenfluramine-associated pulmonary hypertension (MIM#178600) and pulmonary venoocclusive disease 1 (MIM#265450). However, gain of function has been noted in relation to upregulation of p38 MAPK-dependent pro-proliferative pathways and dominant negative has also been suggested as a mechanism in relation to SMAD signalling (OMIM). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Incomplete penetrance has been reported for pulmonary arterial hypertension (PMID: 33380512). (I) 0115 - Variants in this gene are known to have variable expressivity (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2 & v3) <0.001 for a dominant condition (13 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (p.(Arg303Cys): 2 heterozygotes, 0 homozygotes). (I) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0600 - Variant is located in the annotated protein kinase domain (UniProt). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The p.(Arg303Cys) variant has been reported in one individual with congenital heart disease and pulmonary arterial hypertension (PMID: 27002414). (SP) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. This variant has been reported in one individual with pulmonary arterial hypertension (PMID: 16429395). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Mutant constructs carrying the p.(Arg303His) variant were retained in the endoplasmic reticulum compared to WT constructs that were localised to the plasma membrane. Additionally, mutant protein also demonstrated incomplete post-translational modification compared to WT protein (PMID: 25688877). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Pathogenic, no assertion criteria provided | literature only | Rare Disease Genomics Group, St George's University of London | - | - - |
Pulmonary venoocclusive disease 1;C4552070:Pulmonary hypertension, primary, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 19, 2021 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Jan 21, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Pathogenic
DEOGEN2
Benign
T;.;.
Eigen
Uncertain
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D
M_CAP
Benign
D
MetaRNN
Uncertain
T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;L;.
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;N;.
REVEL
Uncertain
Sift
Benign
T;D;.
Sift4G
Benign
T;T;.
Polyphen
D;.;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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Score
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at