Variant: NM_001204.7(BMPR2):c.1587-7_1587-4del

CA2061411

425961 (ClinVar)

Gene: BMPR2

Condition: pulmonary arterial hypertension

Inheritance Mode: Autosomal dominant inheritance

UUID: 226b8aef-8e16-4253-a236-11dd42f5bd8c

Approved on: 2024-09-10

Published on: 2024-09-10

HGVS expressions

NM_001204.7:c.1587-7_1587-4del
NM_001204.7(BMPR2):c.1587-7_1587-4del
NC_000002.12:g.202555245_202555248del
CM000664.2:g.202555245_202555248del
NC_000002.11:g.203419968_203419971del
CM000664.1:g.203419968_203419971del
NC_000002.10:g.203128213_203128216del
NG_009363.1:g.183919_183922del
ENST00000374580.10:c.1587-7_1587-4del
ENST00000638587.1:c.1518-7_1518-4del
ENST00000374574.2:c.1586+2357_1586+2360del
ENST00000374580.8:c.1587-7_1587-4del
NM_001204.6:c.1587-7_1587-4del

Likely Benign

• Met criteria codes: BP4 BS1

• Not Met criteria codes: BA1 PP3 PS4 PM2

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

Evidence submitted by expert panel

Pulmonary Hypertension VCEP

The BMPR2 variant c.1587-7_1587-4del is a non-canonical splice site variant on intron 11 predicted to cause deletion of 4 nucleotides. The highest population minor allele frequency in gnomAD v2.1.1 controls is 0.173% (4/2314 alleles) in the Ashkenazi Jewish population which meets the threshold for BS1 (≥0.1%). Thus, PM2 (<0.01%) or BA1 (1%) were not met. The computational splicing predictor Splice AI score was 0.10 for acceptor loss suggesting that the variant has no impact on splicing which meets the criteria for BP4. The variant was only found in one proband with idiopathic pulmonary arterial hypertension (PMID: 26387786), hence PS4 was not applied. BS3 and PS3 were not evaluated as no functional data was available for this variant. In summary, the variant meets the criteria to be classified as likely benign for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: BS1, BP4 (VCEP specification version 1.1.0, 1/18/2024).

Met criteria codes

• BP4: Splice AI score of 0.1 meets the criteria for BP4 (REVEL ≤0.25; Splice AI ≤0.1).
• BS1: Allele frequency >= 0.1% among GnomAD controls, using the subpopulation with the highest frequency and at least 1000 allele counts in the Ashkenazi Jew population (0.173%) in GnomAD v2.1.1 controls. Ashkenazi Jewish population was not considered based on the recommendations by Clingen. The second highest frequency in the African American population (0.001%) did not meet the threshold for BS1 (≥0.1%). The Groupmax filtering allele frequency for this variant in GnomAD v4.1.0 is 0.00002108.

Not Met criteria codes

• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS4: Only one proband with IPAH identified (PMID: 26387786)
• PM2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline