rs1085307274

Positions:

• chr2-202520166-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: This BMPR2 missense variant c.932G>A is predicted to change a glycine residue to a glutamic acid at position 311. This change occurs in the kinase domain, which is a well established functional domain (PM1 is met). It is absent from gnomAD v2.1.1 controls and gnomAD v4.1 (PM2_supporting is met). There are two ClinVar submissions for this variant, but the affected status of one is "unknown" (PS4 not met). Computational evidence for pathogenicity as evaluated by REVEL generated a score of 0.979 indicating that PP3 is met based on the threshold specified by the PH-VCEP >0.75.In summary, the variant meets the criteria to be classified as variant of uncertain significance (VUS) for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM1, PM2_Supp, PP3 (VCEP specification version 1.1, 1/18/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA350340846/MONDO:0015924/125

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BMPR2 NM_001204.7 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:2
• Conservation: PhyloP100: 9.25

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 Uncertain_significance. Variant got 4 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.
• 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.932G>A	p.Gly311Glu	missense_variant	7/13	ENST00000374580.10	NP_001195.2
BMPR2	XM_011511687.2	c.932G>A	p.Gly311Glu	missense_variant	7/13		XP_011509989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BMPR2	ENST00000374580.10	c.932G>A	p.Gly311Glu	missense_variant	7/13	1	NM_001204.7	ENSP00000363708.4
BMPR2	ENST00000374574.2	c.932G>A	p.Gly311Glu	missense_variant	7/12	2		ENSP00000363702.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461594 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727120

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Pulmonary hypertension, primary, 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

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

-

- -

Pulmonary arterial hypertension Uncertain:1

Uncertain significance, reviewed by expert panel

curation

Clingen Pulmonary Hypertension Variant Curation Expert Panel, ClinGen

Sep 10, 2024

This BMPR2 missense variant c.932G>A is predicted to change a glycine residue to a glutamic acid at position 311. This change occurs in the kinase domain, which is a well established functional domain (PM1 is met). It is absent from gnomAD v2.1.1 controls and gnomAD v4.1 (PM2_supporting is met). There are two ClinVar submissions for this variant, but the affected status of one is "unknown" (PS4 not met). Computational evidence for pathogenicity as evaluated by REVEL generated a score of 0.979 indicating that PP3 is met based on the threshold specified by the PH-VCEP >0.75. In summary, the variant meets the criteria to be classified as variant of uncertain significance (VUS) for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM1, PM2_Supp, PP3 (VCEP specification version 1.1, 1/18/2024). -

Primary pulmonary hypertension Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 31, 2022

ClinVar contains an entry for this variant (Variation ID: 425844). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BMPR2 protein function. This missense change has been observed in individual(s) with pulmonary hypertension (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 311 of the BMPR2 protein (p.Gly311Glu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	H;H;.
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-7.5	D;D;.
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D;.
Sift4G	Uncertain	0.0040	D;D;.
Polyphen		1.0	D;.;.
Vest4		0.98
MutPred		0.92		Loss of methylation at R310 (P = 0.0492);Loss of methylation at R310 (P = 0.0492);.;
MVP		0.99
MPC		1.2
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.98
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs1085307274; hg19: chr2-203384889;