rs1085308078

Positions:

• chr2-202532613-A-T
• chr2-202532613-A-C
• chr2-202532613-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PP3 PM2_Supporting PM1_Strong PM5_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1157A>T (p.Glu386Val) variant is harboured in exon 9 of the BMPR2 gene, encoding the functionally relevant catalytic kinase domain and impacts an amino acid indispensable to kinase structure and function (PM1_strong). This variant is absent from gnomAD v2.1.1 (controls) and v4.1 (PM2_supporting). The variant has been reported once in an FPAH subject (PMID:18364108) (PS4 not met). The REVEL prediction algorithm score is 0.99, the AlphaMissense score is 0.996 indicating pathogenicity (PP3_met). PS2 was not assessed due to lack of paternity data. Functional studies have not been conducted for this variant (PS3 not assessed). Four additional likely pathogenic variants (p.Glu386Ala/Gln/Gly/Lys) have been reported at the same position (PMIDs: 18503968, 21801371, 23675998 and 26387786) (PM5_supporting). In summary, this 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, PM2_supporting, PM5_supporting, PP3 (VCEP specification version 1.1.0, 1/18/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA350341741/MONDO:0015924/125

• Frequency: Genomes: not found (cov: 31)
• Consequence: BMPR2 NM_001204.7 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 8.99

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_pathogenic. Variant got 7 ACMG points.

• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: 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/exons	MANE	Protein	UniProt
BMPR2	NM_001204.7	c.1157A>T	p.Glu386Val	missense_variant	9/13	ENST00000374580.10	NP_001195.2
BMPR2	XM_011511687.2	c.1157A>T	p.Glu386Val	missense_variant	9/13		XP_011509989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BMPR2	ENST00000374580.10	c.1157A>T	p.Glu386Val	missense_variant	9/13	1	NM_001204.7	ENSP00000363708.4
BMPR2	ENST00000374574.2	c.1157A>T	p.Glu386Val	missense_variant	9/12	2		ENSP00000363702.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Pulmonary arterial hypertension Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

Clingen Pulmonary Hypertension Variant Curation Expert Panel, ClinGen

Nov 06, 2024

The c.1157A>T (p.Glu386Val) variant is harboured in exon 9 of the BMPR2 gene, encoding the functionally relevant catalytic kinase domain and impacts an amino acid indispensable to kinase structure and function (PM1_strong). This variant is absent from gnomAD v2.1.1 (controls) and v4.1 (PM2_supporting). The variant has been reported once in an FPAH subject (PMID: 18364108) (PS4 not met). The REVEL prediction algorithm score is 0.99, the AlphaMissense score is 0.996 indicating pathogenicity (PP3_met). PS2 was not assessed due to lack of paternity data. Functional studies have not been conducted for this variant (PS3 not assessed). Four additional likely pathogenic variants (p.Glu386Ala/Gln/Gly/Lys) have been reported at the same position (PMIDs: 18503968, 21801371, 23675998 and 26387786) (PM5_supporting). In summary, this 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, PM2_supporting, PM5_supporting, PP3 (VCEP specification version 1.1.0, 1/18/2024). -

Pulmonary hypertension, primary, 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Rare Disease Genomics Group, St George's University of London

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.66	D;.;.
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.0	H;H;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-6.8	D;D;.
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D;D;.
Sift4G	Uncertain	0.0030	D;D;.
Polyphen		1.0	D;.;.
Vest4		0.98
MutPred		0.98		Gain of catalytic residue at E389 (P = 0.0487);Gain of catalytic residue at E389 (P = 0.0487);.;
MVP		1.0
MPC		1.2
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.98
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs1085307307; hg19: chr2-203397336;