rs1060502583
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 5P and 8B. PM2PP2PP3_ModerateBP6_Very_Strong
The NM_001204.7(BMPR2):c.1509A>C(p.Glu503Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
BMPR2
NM_001204.7 missense
NM_001204.7 missense
Scores
4
9
6
Clinical Significance
Conservation
PhyloP100: 1.92
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 -3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, BMPR2
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.85
BP6
?
Variant 2-202552811-A-C is Benign according to our data. Variant chr2-202552811-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 409828.Status of the report is reviewed_by_expert_panel, 3 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BMPR2 | NM_001204.7 | c.1509A>C | p.Glu503Asp | missense_variant | 11/13 | ENST00000374580.10 | |
BMPR2 | XM_011511687.2 | c.1509A>C | p.Glu503Asp | missense_variant | 11/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BMPR2 | ENST00000374580.10 | c.1509A>C | p.Glu503Asp | missense_variant | 11/13 | 1 | NM_001204.7 | P1 | |
BMPR2 | ENST00000374574.2 | c.1509A>C | p.Glu503Asp | missense_variant | 11/12 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251488Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135918
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461884Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 727244
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Likely benign
Submissions summary: Pathogenic:1Uncertain:3Benign:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Pulmonary arterial hypertension associated with congenital heart disease Pathogenic:1Uncertain:1
Pathogenic, no assertion criteria provided | literature only | Rare Disease Genomics Group, St George's University of London | - | - - |
Uncertain significance, criteria provided, single submitter | case-control | Wendy Chung Laboratory, Columbia University Medical Center | Jun 27, 2018 | - - |
Pulmonary venoocclusive disease 1;C4552070:Pulmonary hypertension, primary, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 09, 2022 | - - |
Primary pulmonary hypertension Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 11, 2016 | This sequence change replaces glutamic acid with aspartic acid at codon 503 of the BMPR2 protein (p.Glu503Asp). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been reported in two individuals affected with pulmonary arterial hypertension (PMID: 15358693, Invitae). Experimental studies have shown that this missense change does not affect BMPR2 localization or signaling, but the clinical significance of these observations is uncertain (PMID: 18321866, 25688877). In summary, this variant is a rare missense change that is not shown to affect protein function. While it is absent from the population and reported in affected individuals, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Pulmonary arterial hypertension Benign:1
Likely benign, reviewed by expert panel | curation | Clingen Pulmonary Hypertension Variant Curation Expert Panel, ClinGen | May 03, 2024 | The NM_001204.7(BMPR2) c.1509A>C variant is a missense variant predicted to cause substitution of glutamate by aspartate at amino acid 503 (p.Glu503Asp). The highest population minor allele frequency in gnomAD v2.1.1 (controls) is 0.0001105 (1/9046 alleles) in East Asian population, which is higher than the ClinGen PH VCEP threshold (<0.01%) for PM2 but lower than the threshold (>0.1%) for BS1. Therefore, this variant does not meet either of these population criteria. The computational predictor REVEL gives a score of 0.662, which is neither above nor below the thresholds predicting a damaging or benign impact on BMPR2 function. Luciferase assay data indicated that variant transcriptional activity was comparable to wild-type, indicating no deleterious effect (BS3; PMID: 18321866). The p.Glu503Asp (p.E503D) mutant also shows normal localization to the plasma membrane (PMID: 25688877) and no effect on cell viability (PMID: 30809644). In summary, this variant meets the criteria to be classified as likely benign for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: BS3. (VCEP specifications version 1.1, 1/18/2024) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Benign
Dann
Uncertain
DEOGEN2
Uncertain
D;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
T
MutationAssessor
Benign
N;N;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;.
REVEL
Pathogenic
Sift
Uncertain
D;T;.
Sift4G
Uncertain
D;T;.
Polyphen
P;.;.
Vest4
MutPred
Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);.;
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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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