Evidence Repository - GenboreeKB

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+3A>T

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA645293834

425913 (ClinVar)

Gene: BMPR2

Condition: pulmonary arterial hypertension

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 4f42c72a-405d-4dd4-8f25-0cdb87adc950

Approved on: 2025-04-29

Published on: 2025-04-29

HGVS expressions

NM_001204.7:c.1276+3A>T

NM_001204.7(BMPR2):c.1276+3A>T

NC_000002.12:g.202532735A>T

CM000664.2:g.202532735A>T

NC_000002.11:g.203397458A>T

CM000664.1:g.203397458A>T

NC_000002.10:g.203105703A>T

NG_009363.1:g.161409A>T

ENST00000374580.10:c.1276+3A>T

ENST00000638587.1:c.1207+3A>T

ENST00000374574.2:c.1276+3A>T

ENST00000374580.8:c.1276+3A>T

NM_001204.6:c.1276+3A>T

Likely Pathogenic

PM2_Supporting PP3 PS1_Supporting PM1_Strong

BP4 BA1 BS1

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+3A>T variant is a non-canonical splice site (+3) 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 heritable PAH (PMID: 20534176). In silico prediction (SpliceAI = 0.97) indicates the variant will probably impact splicing with loss of the canonical donor site in intron 9 (PP3). This predicted splicing event matches a known likely pathogenic variant (c.1276+4A>G) within the same donor site (PS1_supporting) (PMID: 37352859). Exon skipping or use of a cryptic splice site would disrupt the region encoding the conserved intracellular kinase domain (PM1_strong). No familial segregation data were available, and no functional analysis has been reported for this variant. 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: PM1_strong, PS1_supporting, PM2_supporting, PP3 (VCEP specification version v1.1, 1/18/2024).

PM2_Supporting

Variant is absent from gnomAD (v2.1.1 and v4.1.0) control populations

PP3

In silico prediction using SpliceAI indicates the variant will impact splicing with a donor loss score of 0.97, which meets the threshold for pathogenicity (SpliceAI ≥0.2)

PS1_Supporting

The predicted splicing event matches a known likely pathogenic variant (c.1276+4A>G) within the same non-canonical donor splice site. PS1_Supporting applied according to the recommendations from the ClinGen SVI Splicing Subgroup (Walker et al. 2023)

PM1_Strong

The variant is located within the region encoding the conserved intracellular kinase domain (aa. 203–504, exons 5–11). The predicted mis-splicing would disrupt part of the kinase domain critical for protein function

BP4

SpliceAI prediction supports a deleterious impact on splicing (SpliceAI ≥0.2)

BA1

Variant is not present in gnomAD (v2.1.1 and v4.1.0) control populations

BS1

Variant is not present in gnomAD (v2.1.1 and v4.1.0) control populations

Curation History

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