rs1553503554
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP2PP3
The NM_001204.7(BMPR2):c.340C>T(p.Arg114Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000688 in 1,453,966 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 Uncertain significance (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Consequence
BMPR2
NM_001204.7 missense
NM_001204.7 missense
Scores
11
7
1
Clinical Significance
Conservation
PhyloP100: 6.54
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_pathogenic. Variant got 6 ACMG points.
PM1
?
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001204.7
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, 0.78
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BMPR2 | NM_001204.7 | c.340C>T | p.Arg114Cys | missense_variant | 3/13 | ENST00000374580.10 | |
BMPR2 | XM_011511687.2 | c.340C>T | p.Arg114Cys | missense_variant | 3/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BMPR2 | ENST00000374580.10 | c.340C>T | p.Arg114Cys | missense_variant | 3/13 | 1 | NM_001204.7 | P1 | |
BMPR2 | ENST00000374574.2 | c.340C>T | p.Arg114Cys | missense_variant | 3/12 | 2 | |||
BMPR2 | ENST00000479069.1 | n.247C>T | non_coding_transcript_exon_variant | 2/3 | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251460Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135904
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GnomAD4 exome AF: 6.88e-7 AC: 1AN: 1453966Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 723738
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GnomAD4 genome ? Cov.: 32
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Cov.:
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Primary pulmonary hypertension Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 10, 2017 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with BMPR2-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with cysteine at codon 114 of the BMPR2 protein (p.Arg114Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;M;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;.
REVEL
Pathogenic
Sift
Uncertain
D;D;.
Sift4G
Uncertain
D;D;.
Polyphen
D;.;.
Vest4
MutPred
Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);.;
MVP
MPC
ClinPred
D
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