NM_001204.7:c.-930G>A

Variant names:

• chr2-202376545-G-A
• rs3044175
• NM_001204.7:c.-930G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001204.7(BMPR2):​c.-930G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000107 in 140,578 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.00011 (0 hom., cov: 26)
• Consequence: BMPR2 NM_001204.7 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0750
• Publications: 1 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BS2: High AC in GnomAd4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMPR2	NM_001204.7	c.-930G>A		5_prime_UTR_variant	Exon 1 of 13	ENST00000374580.10	NP_001195.2
BMPR2	XM_011511687.2	c.-930G>A		5_prime_UTR_variant	Exon 1 of 13		XP_011509989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMPR2	ENST00000374580.10	c.-930G>A		5_prime_UTR_variant	Exon 1 of 13	1	NM_001204.7	ENSP00000363708.4
ENSG00000273456	ENST00000724884.1	n.154+246C>T		intron_variant	Intron 1 of 1
ENSG00000273456	ENST00000724885.1	n.106+88C>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.000107 AC: 15 AN: 140466 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.0000798

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000450

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000433

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000614

Gnomad OTH AF: 0.00

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

GnomAD4 genome AF: 0.000107 AC: 15 AN: 140578 Hom.: 0 Cov.: 26 AF XY: 0.000118 AC XY: 8 AN XY: 67790

African (AFR) AF: 0.0000795 AC: 3 AN: 37722

American (AMR) AF: 0.000449 AC: 6 AN: 13358

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3386

East Asian (EAS) AF: 0.000435 AC: 2 AN: 4602

South Asian (SAS) AF: 0.00 AC: 0 AN: 3528

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9956

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.0000614 AC: 4 AN: 65110

Other (OTH) AF: 0.00 AC: 0 AN: 1770

Alfa AF: 0.00110 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Pulmonary hypertension, primary, 1 Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	8.6
DANN	Benign	0.96
PhyloP100		0.075
PromoterAI		-0.0017	Neutral

Splicing

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

Other links and lift over

dbSNP: rs3044175; hg19: chr2-203241268;