rs370120266

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP2PP5

The NM_001204.7(BMPR2):​c.71C>A​(p.Ala24Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000031 in 1,614,006 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

BMPR2
NM_001204.7 missense

Scores

5
14

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 4.46
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

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.
PP5
Variant 2-202377545-C-A is Pathogenic according to our data. Variant chr2-202377545-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 425687.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.71C>A p.Ala24Glu missense_variant 1/13 ENST00000374580.10
BMPR2XM_011511687.2 linkuse as main transcriptc.71C>A p.Ala24Glu missense_variant 1/13

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
BMPR2ENST00000374580.10 linkuse as main transcriptc.71C>A p.Ala24Glu missense_variant 1/131 NM_001204.7 P1Q13873-1
BMPR2ENST00000374574.2 linkuse as main transcriptc.71C>A p.Ala24Glu missense_variant 1/122 Q13873-2

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152222
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000400
AC:
1
AN:
250006
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135458
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000889
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461784
Hom.:
0
Cov.:
31
AF XY:
0.00000275
AC XY:
2
AN XY:
727200
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000360
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152222
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74360
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

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
Benign
0.29
BayesDel_addAF
Uncertain
0.033
T
BayesDel_noAF
Benign
-0.19
CADD
Benign
22
DANN
Benign
0.69
DEOGEN2
Uncertain
0.50
D;.
Eigen
Benign
-0.53
Eigen_PC
Benign
-0.38
FATHMM_MKL
Benign
0.42
N
LIST_S2
Benign
0.15
T;T
M_CAP
Uncertain
0.24
D
MetaRNN
Uncertain
0.49
T;T
MetaSVM
Benign
-0.48
T
MutationAssessor
Benign
0.0
N;N
MutationTaster
Benign
0.99
N;N
PrimateAI
Benign
0.47
T
PROVEAN
Benign
-1.1
N;N
REVEL
Uncertain
0.39
Sift
Benign
0.40
T;T
Sift4G
Benign
0.29
T;T
Polyphen
0.047
B;.
Vest4
0.56
MutPred
0.37
Gain of solvent accessibility (P = 0.0145);Gain of solvent accessibility (P = 0.0145);
MVP
0.72
MPC
0.39
ClinPred
0.087
T
GERP RS
3.6
Varity_R
0.11
gMVP
0.62

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: rs370120266; hg19: chr2-203242268; COSMIC: COSV65808844; COSMIC: COSV65808844; API