chr4-95089758-T-C

Variant names:

• chr4-95089758-T-C
• rs1434549
• NM_001203.3:c.-17-14650T>C

Variant summary

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

The NM_001203.3(BMPR1B):​c.-17-14650T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.331 in 151,886 control chromosomes in the GnomAD database, including 8,331 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 0.33 (8331 hom., cov: 31)
• Consequence: BMPR1B NM_001203.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.968
• Publications: 3 publications found

Genes affected

BMPR1B (HGNC:1077): (bone morphogenetic protein receptor type 1B) This gene encodes a member of the bone morphogenetic protein (BMP) receptor family of transmembrane serine/threonine kinases. The ligands of this receptor are BMPs, which 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 2 different types of serine (threonine) kinase receptors: type I receptors of about 50-55 kD and type II receptors of about 70-80 kD. Type II receptors bind ligands in the absence of type I receptors, but they require their respective type I receptors for signaling, whereas type I receptors require their respective type II receptors for ligand binding. Mutations in this gene have been associated with primary pulmonary hypertension. Several transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Feb 2012]

BMPR1B Gene-Disease associations (from GenCC):

• brachydactyly type A2

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• acromesomelic dysplasia 3

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• brachydactyly

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• brachydactyly type A1D

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• brachydactyly type A1

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• acromesomelic dysplasia 2A

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• acromesomelic dysplasia 2B

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• pulmonary arterial hypertension

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.384 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMPR1B	NM_001203.3	c.-17-14650T>C		intron_variant	Intron 3 of 12	ENST00000515059.6	NP_001194.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMPR1B	ENST00000515059.6	c.-17-14650T>C		intron_variant	Intron 3 of 12	1	NM_001203.3	ENSP00000426617.1

Frequencies

GnomAD3 genomes AF: 0.331 AC: 50221 AN: 151770 Hom.: 8325 Cov.: 31

Gnomad AFR AF: 0.296

Gnomad AMI AF: 0.328

Gnomad AMR AF: 0.392

Gnomad ASJ AF: 0.402

Gnomad EAS AF: 0.267

Gnomad SAS AF: 0.321

Gnomad FIN AF: 0.293

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.345

Gnomad OTH AF: 0.349

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

GnomAD4 genome AF: 0.331 AC: 50251 AN: 151886 Hom.: 8331 Cov.: 31 AF XY: 0.330 AC XY: 24519 AN XY: 74250

African (AFR) AF: 0.296 AC: 12254 AN: 41444

American (AMR) AF: 0.392 AC: 5976 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.402 AC: 1393 AN: 3462

East Asian (EAS) AF: 0.267 AC: 1379 AN: 5166

South Asian (SAS) AF: 0.322 AC: 1548 AN: 4812

European-Finnish (FIN) AF: 0.293 AC: 3099 AN: 10568

Middle Eastern (MID) AF: 0.442 AC: 129 AN: 292

European-Non Finnish (NFE) AF: 0.345 AC: 23438 AN: 67882

Other (OTH) AF: 0.349 AC: 736 AN: 2106

Alfa AF: 0.325 Hom.: 1043

Bravo AF: 0.336

Asia WGS AF: 0.274 AC: 950 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	12
DANN	Benign	0.90
PhyloP100		0.97
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: rs1434549; hg19: chr4-96010909;