Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_001204.7(BMPR2):c.1276+4A>G

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA645293835

425914 (ClinVar)

Gene: BMPR2

Condition: pulmonary arterial hypertension

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 0e88338c-6f77-4186-8f0e-0e9635aeb1ea

Approved on: 2025-04-29

Published on: 2025-04-29

HGVS expressions

NM_001204.7:c.1276+4A>G

NM_001204.7(BMPR2):c.1276+4A>G

NC_000002.12:g.202532736A>G

CM000664.2:g.202532736A>G

NC_000002.11:g.203397459A>G

CM000664.1:g.203397459A>G

NC_000002.10:g.203105704A>G

NG_009363.1:g.161410A>G

ENST00000374580.10:c.1276+4A>G

ENST00000638587.1:c.1207+4A>G

ENST00000374574.2:c.1276+4A>G

ENST00000374580.8:c.1276+4A>G

NM_001204.6:c.1276+4A>G

Likely Pathogenic

PM2_Supporting PVS1

BA1 BS1 BP4 PS4

Evidence Links 0

Expert Panel

Pulmonary Hypertension VCEP

Criteria Specification Information

Criteria Specification: ClinGen Pulmonary Hypertension Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BMPR2 Version 1.1.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Pulmonary Hypertension VCEP

The BMPR2 c.1276+4A>G variant is a non-canonical splice site (+4) variant located in intron 9. The variant is absent from gnomAD v.2.1.1 and v4.1.0 (PM2_supporting) and was reported in a single proband with PAH (PMID: 16429395). An in vitro exon trapping assay (including wild-type exon 9, or missense or c.1267+4A>G mutant exon 9) demonstrated exon skipping with the non-canonical splice variant (PMID: 18321866). Further, in silico prediction (SpliceAI = 0.59) indicates the variant will probably impact splicing with loss of the canonical donor site in intron 9. Exon skipping or use of a cryptic splice site would lead to nonsense-mediated decay or disrupt the region encoding the conserved intracellular kinase domain, respectively. Taken together, the data support the application of PVS1 instead of PP3 and PM1 (PMID: 37352859). No familial segregation data were available. In summary, the variant meets the criteria to be classified as likely pathogenic for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PVS1, PM2_supporting, (VCEP specification version v1.1, 1/18/2024).

PM2_Supporting

Variant is absent from both gnomAD v2.1.1 and gnomAD v4.1.0.

PVS1

Exon trapping assay was performed by transfecting a pTN132 construct of c.1276+4G>A into HEK293 cell lines. The assay showed skipping of exon 9, predicting to cause a frameshift leading to nonsense mediated decay (PMID: 18321866). These data were supported by a SpliceAI score of 0.59 predicting donor loss of the canonical splice motif. PVS1 was applied by considering following points: -Splice AI score (0.59) indicating splice donor loss -Experimental data confirming exon 9 skipping -Presence of exon 9 in critical well-established functional kinase domain

BA1

Variant is absent from both gnomAD v2.1.1 and gnomAD v4.1.0.

BS1

Variant is absent from both gnomAD v2.1.1 and gnomAD v4.1.0.

BP4

PVS1 was applied, partly based on the Splice AI score of 0.59 predicting donor loss in the canonical splice site of intron 9.

PS4

The variant was present only in one proband with primary pulmonary hypertension (PMID:16429395)

Curation History

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