rs1085307154

chr2-202377522-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001204.7(BMPR2):c.48G>A(p.Trp16Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BMPR2 NM_001204.7 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 0.667

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 278 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-202377522-G-A is Pathogenic according to our data. Variant chr2-202377522-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 425685.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BMPR2	NM_001204.7	c.48G>A	p.Trp16Ter	stop_gained	1/13	ENST00000374580.10
BMPR2	XM_011511687.2	c.48G>A	p.Trp16Ter	stop_gained	1/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMPR2	ENST00000374580.10	c.48G>A	p.Trp16Ter	stop_gained	1/13	1	NM_001204.7	P1
BMPR2	ENST00000374574.2	c.48G>A	p.Trp16Ter	stop_gained	1/12	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pulmonary hypertension, primary, 1 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	Rare Disease Genomics Group, St George's University of London	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Mar 13, 2022	- -

Pulmonary arterial hypertension Pathogenic:1

Pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

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Primary pulmonary hypertension Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 30, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 425685). This premature translational stop signal has been observed in individual(s) with pulmonary arterial hypertension (PMID: 18356561, 21801371, 26387786). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp16*) in the BMPR2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BMPR2 are known to be pathogenic (PMID: 16429395). -

BMPR2-related condition Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 07, 2024

The BMPR2 c.48G>A variant is predicted to result in premature protein termination (p.Trp16*). This variant has been reported in multiple individuals with idiopathic or hereditary pulmonary arterial hypertension (Sztrymf et al. 2008. PubMed ID: 18356561; Dewachter et al. 2009. PubMed ID: 19324947; Liu et al. 2011. PubMed ID: 21737554; Pfarr et al. 2011. PubMed ID: 21801371; Machado et al. 2015. PubMed ID: 26387786; Table S1, Eichstaedt et al. 2022. PubMed ID: 35346192). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in BMPR2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.29
Cadd	Pathogenic	35
Dann	Uncertain	0.98
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Benign	0.094	N
MutationTaster	Benign	1.0	A;A
Vest4		0.62
GERP RS		2.5

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

Other links and lift over

dbSNP: rs1085307154; hg19: chr2-203242245; COSMIC: COSV65809003; COSMIC: COSV65809003;