rs1085307323

Positions:

• chr2-202532713-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: BMPR2 c.1257A>T is a missense variant predicted to cause substitution of arginine to serine at amino acid position 419 (p.Arg419Ser). The variant is absent from gnomAD v2.1.1 controls and found at a maximum allele frequency of 0.000022 in gnomAD v4.1.0 in the East Asian ancestry group, meeting PM2_supporting criterion of <0.01% (BA1 and BS1 not met). The REVEL score of 0.59 does not meet BP4 (<=0.25) or PP3 (>=0.75) criteria. This variant resides within the critical kinase domain (PM1_moderate met). Co-segregation/case, experimental criteria, and alternative missense variants at the same location were not evaluated due to lack of reported evidence. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM2_supporting, PM1_moderate (VCEP specification version 1.1.0, 1/18/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA350341975/MONDO:0015924/125

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BMPR2 NM_001204.7 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1
• Conservation: PhyloP100: 1.50

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 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BMPR2	NM_001204.7	c.1257A>T	p.Arg419Ser	missense_variant	9/13	ENST00000374580.10	NP_001195.2
BMPR2	XM_011511687.2	c.1257A>T	p.Arg419Ser	missense_variant	9/13		XP_011509989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BMPR2	ENST00000374580.10	c.1257A>T	p.Arg419Ser	missense_variant	9/13	1	NM_001204.7	ENSP00000363708.4
BMPR2	ENST00000374574.2	c.1257A>T	p.Arg419Ser	missense_variant	9/12	2		ENSP00000363702.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460836 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726794

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

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

Jan 03, 2025

BMPR2 c.1257A>T is a missense variant predicted to cause substitution of arginine to serine at amino acid position 419 (p.Arg419Ser). The variant is absent from gnomAD v2.1.1 controls and found at a maximum allele frequency of 0.000022 in gnomAD v4.1.0 in the East Asian ancestry group, meeting PM2_supporting criterion of <0.01% (BA1 and BS1 not met). The REVEL score of 0.59 does not meet BP4 (<=0.25) or PP3 (>=0.75) criteria. This variant resides within the critical kinase domain (PM1_moderate met). Co-segregation/case, experimental criteria, and alternative missense variants at the same location were not evaluated due to lack of reported evidence. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM2_supporting, PM1_moderate (VCEP specification version 1.1.0, 1/18/2024). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D;.;.
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Benign	0.080	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Benign	-0.47	T
MutationAssessor	Uncertain	2.2	M;M;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-5.8	D;D;.
REVEL	Uncertain	0.59
Sift	Uncertain	0.010	D;D;.
Sift4G	Uncertain	0.0050	D;D;.
Polyphen		1.0	D;.;.
Vest4		0.94
MutPred		0.90		Loss of solvent accessibility (P = 0.1077);Loss of solvent accessibility (P = 0.1077);.;
MVP		0.98
MPC		1.1
ClinPred		1.0	D
GERP RS		0.0012
Varity_R		0.94
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1085307323; hg19: chr2-203397436;