rs140683387
Positions:
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 3P and 8B. PM1PP2BP4_StrongBS2
The NM_001204.7(BMPR2):āc.276A>Cā(p.Gln92His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000779 in 1,565,690 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.000033 ( 0 hom., cov: 32)
Exomes š: 0.000083 ( 0 hom. )
Consequence
BMPR2
NM_001204.7 missense
NM_001204.7 missense
Scores
2
6
11
Clinical Significance
Conservation
PhyloP100: 0.115
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 -5 ACMG points.
PM1
?
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_001204.7
PP2
?
Missense variant where missense usually causes diseases, BMPR2
BP4
?
Computational evidence support a benign effect (MetaRNN=0.051796854).
BS2
?
High AC in GnomAd4 at 5 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BMPR2 | NM_001204.7 | c.276A>C | p.Gln92His | missense_variant | 3/13 | ENST00000374580.10 | |
BMPR2 | XM_011511687.2 | c.276A>C | p.Gln92His | missense_variant | 3/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BMPR2 | ENST00000374580.10 | c.276A>C | p.Gln92His | missense_variant | 3/13 | 1 | NM_001204.7 | P1 | |
BMPR2 | ENST00000374574.2 | c.276A>C | p.Gln92His | missense_variant | 3/12 | 2 | |||
BMPR2 | ENST00000479069.1 | n.183A>C | non_coding_transcript_exon_variant | 2/3 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152108Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000557 AC: 14AN: 251434Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135908
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GnomAD4 exome AF: 0.0000828 AC: 117AN: 1413464Hom.: 0 Cov.: 31 AF XY: 0.0000822 AC XY: 58AN XY: 705688
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Pulmonary hypertension, primary, 1 Uncertain:2
Uncertain significance, no assertion criteria provided | literature only | Rare Disease Genomics Group, St George's University of London | - | - - |
Uncertain significance, criteria provided, single submitter | reference population | Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center | Mar 18, 2016 | - - |
Pulmonary venoocclusive disease 1;C4552070:Pulmonary hypertension, primary, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Nov 15, 2021 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 19, 2020 | Present in two Japanese patients reported to have pulmonary arterial hypertension and in a patient with anomalous unilateral single pulmonary vein (Kabata et al., 2013; Koyama et al., 2014; Kobayashi et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29718794, 24583436, 23675998, 27002414) - |
Primary pulmonary hypertension Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
D;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Benign
T;T;T
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T;T
MetaSVM
Uncertain
T
MutationAssessor
Benign
N;N;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;.
REVEL
Uncertain
Sift
Benign
T;T;.
Sift4G
Benign
T;T;.
Polyphen
B;.;.
Vest4
MutPred
Loss of helix (P = 0.079);Loss of helix (P = 0.079);.;
MVP
MPC
ClinPred
T
GERP RS
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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