rs1085307151

Variant names:

• chr2-202377512-G-A
• rs1085307151
• NM_001204.7:c.38G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-202377512-G-A
• chr2-202377512-G-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_001204.7(BMPR2):​c.38G>A​(p.Trp13*) 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:3
• Conservation: PhyloP100: 0.798

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 14 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 6 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-202377512-G-A is Pathogenic according to our data. Variant chr2-202377512-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 425682.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	c.38G>A	p.Trp13*	stop_gained	Exon 1 of 13	ENST00000374580.10	NP_001195.2
BMPR2	XM_011511687.2	c.38G>A	p.Trp13*	stop_gained	Exon 1 of 13		XP_011509989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMPR2	ENST00000374580.10	c.38G>A	p.Trp13*	stop_gained	Exon 1 of 13	1	NM_001204.7	ENSP00000363708.4
BMPR2	ENST00000374574.2	c.38G>A	p.Trp13*	stop_gained	Exon 1 of 12	2		ENSP00000363702.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Feb 02, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BMPR2 c.38G>A; p.Trp13Ter variant (rs1085307151) is reported in the literature in individuals affected with pulmonary arterial hypertension (Chida 2012, Machado 2015). This variant is also reported in ClinVar (Variation ID: 425682), but is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay (NMD). Additionally, another variant at this codon (c.39G>A; p.Trp13Ter) has been reported in a family with pulmonary arterial hypertension and is considered pathogenic (Hamid 2010). In vitro functional analyses of the c.39G>A variant show that while the transcript does not undergo NMD, the variant results in a truncated protein missing the ligand binding domain and part of the transmembrane domain (Hamid 2010). Based on available information, the c.38G>A; p.Trp13Ter variant is considered to be pathogenic. References: Chida A et al. Outcomes of childhood pulmonary arterial hypertension in BMPR2 and ALK1 mutation carriers. Am J Cardiol. 2012 Aug 15;110(4):586-93. Hamid R et al. Transcripts from a novel BMPR2 termination mutation escape nonsense mediated decay by downstream translation re-initiation: implications for treating pulmonary hypertension. Clin Genet. 2010 Mar;77(3):280-6. Machado RD et al. Pulmonary Arterial Hypertension: A Current Perspective on Established and Emerging Molecular Genetic Defects. Hum Mutat. 2015 Dec;36(12):1113-27. -

Primary pulmonary hypertension Pathogenic:1

Aug 12, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 425682). This premature translational stop signal has been observed in individuals with pulmonary arterial hypertension (PMID: 22632830, 26387786). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Trp13*) 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). -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Benign	0.089	N
Vest4		0.60
GERP RS		0.70
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs1085307151; hg19: chr2-203242235;