rs1085307314

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP2PP3_StrongPP5

The NM_001204.7(BMPR2):​c.1220A>C​(p.Tyr407Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y407C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Consequence

BMPR2
NM_001204.7 missense

Scores

15
3
1

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 8.99
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 10 ACMG points.

PM1
In a helix (size 20) in uniprot entity BMPR2_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_001204.7
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), BMPR2. . Gene score misZ 2.0624 (greater than the threshold 3.09). Trascript score misZ 3.2701 (greater than threshold 3.09). GenCC has associacion of gene with pulmonary hypertension, primary, 1, congenital heart disease, heritable pulmonary arterial hypertension, pulmonary arterial hypertension.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.975
PP5
Variant 2-202532676-A-C is Pathogenic according to our data. Variant chr2-202532676-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 425895.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
BMPR2NM_001204.7 linkuse as main transcriptc.1220A>C p.Tyr407Ser missense_variant 9/13 ENST00000374580.10
BMPR2XM_011511687.2 linkuse as main transcriptc.1220A>C p.Tyr407Ser missense_variant 9/13

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
BMPR2ENST00000374580.10 linkuse as main transcriptc.1220A>C p.Tyr407Ser missense_variant 9/131 NM_001204.7 P1Q13873-1
BMPR2ENST00000374574.2 linkuse as main transcriptc.1220A>C p.Tyr407Ser missense_variant 9/122 Q13873-2

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

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
0.99
BayesDel_addAF
Pathogenic
0.57
D
BayesDel_noAF
Pathogenic
0.58
CADD
Pathogenic
32
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.66
D;.;.
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.91
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
D;D;D
M_CAP
Pathogenic
0.42
D
MetaRNN
Pathogenic
0.97
D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.9
H;H;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.91
D
PROVEAN
Pathogenic
-8.7
D;D;.
REVEL
Pathogenic
0.98
Sift
Pathogenic
0.0
D;D;.
Sift4G
Pathogenic
0.0010
D;D;.
Polyphen
1.0
D;.;.
Vest4
0.94
MutPred
0.86
Loss of methylation at K402 (P = 0.0536);Loss of methylation at K402 (P = 0.0536);.;
MVP
0.99
MPC
1.3
ClinPred
1.0
D
GERP RS
5.3
Varity_R
0.98
gMVP
0.97

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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: rs1085307314; hg19: chr2-203397399; API