rs1085307283

chr2-202530794-A-AT

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001204.7(BMPR2):c.969dup(p.His324SerfsTer3) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. D323D) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BMPR2 NM_001204.7 frameshift, splice_region
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.20

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-202530794-A-AT is Pathogenic according to our data. Variant chr2-202530794-A-AT is described in ClinVar as [Pathogenic]. Clinvar id is 425858.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BMPR2	NM_001204.7	c.969dup	p.His324SerfsTer3	frameshift_variant, splice_region_variant	8/13	ENST00000374580.10
BMPR2	XM_011511687.2	c.969dup	p.His324SerfsTer3	frameshift_variant, splice_region_variant	8/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMPR2	ENST00000374580.10	c.969dup	p.His324SerfsTer3	frameshift_variant, splice_region_variant	8/13	1	NM_001204.7	P1
BMPR2	ENST00000374574.2	c.969dup	p.His324SerfsTer3	frameshift_variant, splice_region_variant	8/12	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Primary pulmonary hypertension Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jun 08, 2021

For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with pulmonary arterial hypertension (PMID: 16717148, 31727138). ClinVar contains an entry for this variant (Variation ID: 425858). This variant is also described as c.968_969insT (p.H324fsX3) in the literature. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.His324Serfs*3) in the BMPR2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BMPR2 are known to be pathogenic (PMID: 16429395). -

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

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1085307283; hg19: chr2-203395517;