rs769408722

Variant names:

• chr2-202555237-TTTTC-T
• rs769408722
• NM_001204.7:c.1587-7_1587-4delCTTT

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS1

This summary comes from the ClinGen Evidence Repository: 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). LINK:https://erepo.genome.network/evrepo/ui/classification/CA2061411/MONDO:0015924/125

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000032 (0 hom.)
• Consequence: BMPR2 NM_001204.7 splice_region, intron
• Clinical Significance: Likely benign reviewed by expert panel P:1 B:2
• Conservation: PhyloP100: 3.13

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 Likely_benign. Variant got -5 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: 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.1587-7_1587-4delCTTT		splice_region_variant, intron_variant	Intron 11 of 12	ENST00000374580.10	NP_001195.2
BMPR2	XM_011511687.2	c.1587-7_1587-4delCTTT		splice_region_variant, intron_variant	Intron 11 of 12		XP_011509989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMPR2	ENST00000374580.10	c.1587-14_1587-11delTTTC		intron_variant	Intron 11 of 12	1	NM_001204.7	ENSP00000363708.4
BMPR2	ENST00000374574.2	c.1586+2350_1586+2353delTTTC		intron_variant	Intron 11 of 11	2		ENSP00000363702.2

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000519 AC: 13 AN: 250586 Hom.: 0 AF XY: 0.0000443 AC XY: 6 AN XY: 135552

Gnomad AFR exome AF: 0.0000621

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000695

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000323 AC: 47 AN: 1456712 Hom.: 0 AF XY: 0.0000386 AC XY: 28 AN XY: 725030

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000575

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000581

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000217

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152212 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74358

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000529

ClinVar

Significance: Likely benign

Submissions summary: Pathogenic:1 Benign:2

Revision: reviewed by expert panel

Submissions by phenotype

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 arterial hypertension Benign:1

Sep 10, 2024

Clingen Pulmonary Hypertension Variant Curation Expert Panel, ClinGen

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: curation

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). -

Primary pulmonary hypertension Benign:1

Jan 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs769408722; hg19: chr2-203419960;