rs1060502584

Variant names:

• chr2-202530789-A-G
• rs1060502584
• NM_001204.7:c.968-5A>G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PP3 PM2_Supporting PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_001204.7(BMPR2) c.968-5A>G is an intronic variant at Intron 7. This variant is absent from gnomAD v2.1.1 and v3.1.2 controls (PM2_supporting). It is predicted to create a strong acceptor site gain (PP3_supporting) and PH VCEP internal unpublished RNA sequencing data confirmed an effect on splicing leading to NMD. The c.968-5G>A variant leads to the inclusion of 4 bases of intron 7 into the mature mRNA creating a frameshift and a STOP codon at position 327(PVS1_strong). The variant has been reported in 2 unrelated PAH patients: first proband is associated with the publication (PMID:19555857) and the second proband, with no further information for co-segregation, is from an internal lab contributor (PS4_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PVS1_strong, PM2_supporting, PS4_supporting and PP3_supporting (VCEP specifications version 1.1, 1/18/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA16610662/MONDO:0015924/125

• Frequency: Genomes: not found (cov: 33)
• Consequence: BMPR2 NM_001204.7 splice_region, intron
• Scores: Splicing: ADA: 0.9982
• Clinical Significance: Pathogenic reviewed by expert panel P:3 U:2
• Conservation: PhyloP100: 2.51

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 11 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMPR2	NM_001204.7	c.968-5A>G		splice_region_variant, intron_variant	Intron 7 of 12	ENST00000374580.10	NP_001195.2
BMPR2	XM_011511687.2	c.968-5A>G		splice_region_variant, intron_variant	Intron 7 of 12		XP_011509989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMPR2	ENST00000374580.10	c.968-5A>G		splice_region_variant, intron_variant	Intron 7 of 12	1	NM_001204.7	ENSP00000363708.4
BMPR2	ENST00000374574.2	c.968-5A>G		splice_region_variant, intron_variant	Intron 7 of 11	2		ENSP00000363702.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Pulmonary arterial hypertension Pathogenic:1

May 03, 2024

Clingen Pulmonary Hypertension Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_001204.7(BMPR2) c.968-5A>G is an intronic variant at Intron 7. This variant is absent from gnomAD v2.1.1 and v3.1.2 controls (PM2_supporting). It is predicted to create a strong acceptor site gain (PP3_supporting) and PH VCEP internal unpublished RNA sequencing data confirmed an effect on splicing leading to NMD. The c.968-5G>A variant leads to the inclusion of 4 bases of intron 7 into the mature mRNA creating a frameshift and a STOP codon at position 327(PVS1_strong). The variant has been reported in 2 unrelated PAH patients: first proband is associated with the publication (PMID: 19555857) and the second proband, with no further information for co-segregation, is from an internal lab contributor (PS4_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PVS1_strong, PM2_supporting, PS4_supporting and PP3_supporting (VCEP specifications version 1.1, 1/18/2024) -

Primary pulmonary hypertension Pathogenic:1

Oct 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 7 of the BMPR2 gene. It does not directly change the encoded amino acid sequence of the BMPR2 protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with pulmonary arterial hypertension (PMID: 19555857; internal data). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this BMPR2 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 19,619 individuals referred to our laboratory for BMPR2 testing. ClinVar contains an entry for this variant (Variation ID: 409829). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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 venoocclusive disease 1 Uncertain:1

Nov 15, 2019

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not provided Uncertain:1

Feb 04, 2022

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS4_Supporting, PP3, PM2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	24
DANN	Benign	0.89

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.85
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.99		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1060502584; hg19: chr2-203395512;