2-202376511-AGGCGGCGGCGGCGGCGGCGGCGGCGGC-AGGCGGCGGCGGCGGCGGCGGCGGC

Variant names:

• chr2-202376511-AGGC-A
• rs375624016
• NM_001204.7:c.-930_-928delGGC

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_001204.7(BMPR2):​c.-930_-928delGGC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0056 (4 hom., cov: 16)
• Consequence: BMPR2 NM_001204.7 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.42
• Publications: 3 publications found

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]

BMPR2 Gene-Disease associations (from GenCC):

• pulmonary arterial hypertension

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• pulmonary hypertension, primary, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• heritable pulmonary arterial hypertension

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ENSG00000273456 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00556 (699/125828) while in subpopulation AFR AF = 0.00888 (302/34000). AF 95% confidence interval is 0.00806. There are 4 homozygotes in GnomAd4. There are 335 alleles in the male GnomAd4 subpopulation. Median coverage is 16. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 699 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001204.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMPR2	NM_001204.7	MANE Select	c.-930_-928delGGC		5_prime_UTR	Exon 1 of 13	NP_001195.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMPR2	ENST00000374580.10	TSL:1 MANE Select	c.-930_-928delGGC		5_prime_UTR	Exon 1 of 13	ENSP00000363708.4	Q13873-1
	ENSG00000273456	ENST00000724884.1		n.154+277_154+279delGCC		intron	N/A
	ENSG00000273456	ENST00000724885.1		n.106+119_106+121delGCC		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00548 AC: 689 AN: 125724 Hom.: 3 Cov.: 16

Gnomad AFR AF: 0.00862

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00237

Gnomad ASJ AF: 0.00314

Gnomad EAS AF: 0.00860

Gnomad SAS AF: 0.00238

Gnomad FIN AF: 0.000971

Gnomad MID AF: 0.00735

Gnomad NFE AF: 0.00513

Gnomad OTH AF: 0.00257

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.00556 AC: 699 AN: 125828 Hom.: 4 Cov.: 16 AF XY: 0.00556 AC XY: 335 AN XY: 60226

African (AFR) AF: 0.00888 AC: 302 AN: 34000

American (AMR) AF: 0.00237 AC: 28 AN: 11822

Ashkenazi Jewish (ASJ) AF: 0.00314 AC: 10 AN: 3186

East Asian (EAS) AF: 0.00863 AC: 36 AN: 4170

South Asian (SAS) AF: 0.00238 AC: 7 AN: 2942

European-Finnish (FIN) AF: 0.000971 AC: 8 AN: 8236

Middle Eastern (MID) AF: 0.00769 AC: 2 AN: 260

European-Non Finnish (NFE) AF: 0.00513 AC: 302 AN: 58914

Other (OTH) AF: 0.00254 AC: 4 AN: 1572

Alfa AF: 0.00208 Hom.: 30

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Pulmonary hypertension, primary, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.4

Splicing

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

Other links and lift over

dbSNP: rs375624016; hg19: chr2-203241234; COSMIC: COSV107485578;