NM_001204.7:c.76+4138G>A

Variant names:

• chr2-202381688-G-A
• rs4303700
• NM_001204.7:c.76+4138G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001204.7(BMPR2):​c.76+4138G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.163 in 152,162 control chromosomes in the GnomAD database, including 2,404 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.16 (2404 hom., cov: 31)
• Consequence: BMPR2 NM_001204.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.23
• Publications: 12 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.221 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMPR2	NM_001204.7	c.76+4138G>A		intron_variant	Intron 1 of 12	ENST00000374580.10	NP_001195.2
BMPR2	XM_011511687.2	c.76+4138G>A		intron_variant	Intron 1 of 12		XP_011509989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMPR2	ENST00000374580.10	c.76+4138G>A		intron_variant	Intron 1 of 12	1	NM_001204.7	ENSP00000363708.4
BMPR2	ENST00000374574.2	c.76+4138G>A		intron_variant	Intron 1 of 11	2		ENSP00000363702.2

Frequencies

GnomAD3 genomes AF: 0.163 AC: 24830 AN: 152044 Hom.: 2403 Cov.: 31

Gnomad AFR AF: 0.0783

Gnomad AMI AF: 0.413

Gnomad AMR AF: 0.163

Gnomad ASJ AF: 0.214

Gnomad EAS AF: 0.0553

Gnomad SAS AF: 0.100

Gnomad FIN AF: 0.141

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.224

Gnomad OTH AF: 0.205

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

GnomAD4 genome AF: 0.163 AC: 24835 AN: 152162 Hom.: 2404 Cov.: 31 AF XY: 0.158 AC XY: 11718 AN XY: 74384

African (AFR) AF: 0.0780 AC: 3239 AN: 41514

American (AMR) AF: 0.162 AC: 2481 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.214 AC: 743 AN: 3470

East Asian (EAS) AF: 0.0556 AC: 288 AN: 5182

South Asian (SAS) AF: 0.0998 AC: 481 AN: 4820

European-Finnish (FIN) AF: 0.141 AC: 1497 AN: 10596

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.224 AC: 15221 AN: 67986

Other (OTH) AF: 0.208 AC: 440 AN: 2114

Alfa AF: 0.210 Hom.: 12352

Bravo AF: 0.165

Asia WGS AF: 0.0840 AC: 291 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.099
DANN	Benign	0.55
PhyloP100		-2.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs4303700; hg19: chr2-203246411;