rs869025367

Positions:

• chr2-202532732-G-A
• chr2-202532732-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Strong

The NM_001204.7(BMPR2):​c.1276G>A​(p.Gly426Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Synonymous variant affecting the same amino acid position (i.e. G426G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: BMPR2 NM_001204.7 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.64

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.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, BMPR2
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BMPR2	NM_001204.7	c.1276G>A	p.Gly426Arg	missense_variant, splice_region_variant	9/13	ENST00000374580.10
BMPR2	XM_011511687.2	c.1276G>A	p.Gly426Arg	missense_variant, splice_region_variant	9/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMPR2	ENST00000374580.10	c.1276G>A	p.Gly426Arg	missense_variant, splice_region_variant	9/13	1	NM_001204.7	P1
BMPR2	ENST00000374574.2	c.1276G>A	p.Gly426Arg	missense_variant, splice_region_variant	9/12	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary pulmonary hypertension Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 03, 2017

This sequence change replaces glycine with arginine at codon 426 of the BMPR2 protein (p.Gly426Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant also falls at the last nucleotide of exon 9 of the BMPR2 coding sequence, which is part of the consensus splice site for this exon. In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a BMPR2-related disease. However, a different variant affecting the same nucleotide and resulting in the same amino acid change (c.1276G>C (p.Gly426Arg)) has been reported in the literature in an individual affected with heritable pulmonary arterial hypertension (PMID: 26387786). Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of nucleotide changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D;.;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Benign	0.078	D
MetaRNN	Pathogenic	0.76	D;D;D
MetaSVM	Uncertain	0.031	D
MutationAssessor	Benign	1.6	L;L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.0	D;D;.
REVEL	Uncertain	0.59
Sift	Benign	0.093	T;T;.
Sift4G	Benign	0.13	T;T;.
Polyphen		0.88	P;.;.
Vest4		0.82
MutPred		0.49		Gain of phosphorylation at S428 (P = 0.0797);Gain of phosphorylation at S428 (P = 0.0797);.;
MVP		0.87
MPC		1.2
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.72
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.98		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs869025367; hg19: chr2-203397455;