rs1085307177

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_001204.7(BMPR2):c.200A>G(p.Tyr67Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,858 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y67F) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

BMPR2
NM_001204.7 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:3O:1

Conservation

PhyloP100: 3.41

Publications

5 publications found

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]

BMPR2 Gene-Disease associations (from GenCC):

pulmonary arterial hypertension
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
pulmonary hypertension, primary, 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
heritable pulmonary arterial hypertension
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
congenital heart disease
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

BMPR2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PM1

In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 11 uncertain in NM_001204.7

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.982

PP5

Variant 2-202464932-A-G is Pathogenic according to our data. Variant chr2-202464932-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 425719.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMPR2	NM_001204.7 link	c.200A>G	p.Tyr67Cys	missense_variant	Exon 2 of 13	ENST00000374580.10	NP_001195.2	Q13873-1
BMPR2	XM_011511687.2 link	c.200A>G	p.Tyr67Cys	missense_variant	Exon 2 of 13		XP_011509989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
BMPR2	ENST00000374580.10 link	c.200A>G	p.Tyr67Cys	missense_variant	Exon 2 of 13	1	NM_001204.7	ENSP00000363708.4	Q13873-1
BMPR2	ENST00000374574.2 link	c.200A>G	p.Tyr67Cys	missense_variant	Exon 2 of 12	2		ENSP00000363702.2	Q13873-2
BMPR2	ENST00000479069.1 link	n.107A>G		non_coding_transcript_exon_variant	Exon 1 of 3	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461858

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727230

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111998

Other (OTH)

AF:

0.00

AC:

AN:

60394

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Pulmonary arterial hypertension

Pathogenic:1

NIHR Bioresource Rare Diseases, University of Cambridge

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Primary pulmonary hypertension

Pathogenic:1

Aug 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 67 of the BMPR2 protein (p.Tyr67Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with pulmonary arterial hypertension (PMID: 15146475, 16429395, 18356561, 20002458). ClinVar contains an entry for this variant (Variation ID: 425719). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt BMPR2 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BMPR2 function (PMID: 25187962). For these reasons, this variant has been classified as Pathogenic. -

Pulmonary hypertension, primary, 1

Pathogenic:1

Rare Disease Genomics Group, St George's University of London

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Pulmonary arterial hypertension;C5679820:Idiopathic and/or familial pulmonary arterial hypertension

Other:1

Wendy Chung Laboratory, Boston Children's Hospital

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.98

D;.;.

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

0.98

D;D;D

M_CAP

Pathogenic

0.45

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.2

M;M;.

PhyloP100

3.4

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-5.9

D;D;.

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0010

D;D;.

Sift4G

Uncertain

0.0060

D;D;.

Polyphen

1.0

D;.;.

Vest4

0.91

MutPred

0.94

Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);.;

MVP

0.98

MPC

1.2

ClinPred

0.99

GERP RS

5.4

Varity_R

0.95

gMVP

0.72

Mutation Taster

=10/90

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over