4-94995128-T-C

Variant names:

• chr4-94995128-T-C
• rs4145993
• NM_001203.3:c.-112-912T>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.-112-912T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.72 in 152,046 control chromosomes in the GnomAD database, including 40,645 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 0.72 (40645 hom., cov: 31)
• Consequence: BMPR1B NM_001203.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.408
• Publications: 6 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=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.843 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMPR1B	NM_001203.3	c.-112-912T>C		intron_variant	Intron 2 of 12	ENST00000515059.6	NP_001194.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMPR1B	ENST00000515059.6	c.-112-912T>C		intron_variant	Intron 2 of 12	1	NM_001203.3	ENSP00000426617.1
BMPR1B	ENST00000672698.1	c.-112-912T>C		intron_variant	Intron 2 of 12			ENSP00000500035.1

Frequencies

GnomAD3 genomes AF: 0.720 AC: 109446 AN: 151928 Hom.: 40623 Cov.: 31

Gnomad AFR AF: 0.514

Gnomad AMI AF: 0.896

Gnomad AMR AF: 0.798

Gnomad ASJ AF: 0.766

Gnomad EAS AF: 0.864

Gnomad SAS AF: 0.818

Gnomad FIN AF: 0.732

Gnomad MID AF: 0.691

Gnomad NFE AF: 0.804

Gnomad OTH AF: 0.721

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

GnomAD4 genome AF: 0.720 AC: 109519 AN: 152046 Hom.: 40645 Cov.: 31 AF XY: 0.722 AC XY: 53648 AN XY: 74320

African (AFR) AF: 0.514 AC: 21303 AN: 41438

American (AMR) AF: 0.799 AC: 12201 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.766 AC: 2661 AN: 3472

East Asian (EAS) AF: 0.864 AC: 4464 AN: 5168

South Asian (SAS) AF: 0.819 AC: 3940 AN: 4812

European-Finnish (FIN) AF: 0.732 AC: 7741 AN: 10572

Middle Eastern (MID) AF: 0.688 AC: 201 AN: 292

European-Non Finnish (NFE) AF: 0.804 AC: 54676 AN: 67990

Other (OTH) AF: 0.717 AC: 1515 AN: 2112

Alfa AF: 0.740 Hom.: 5506

Bravo AF: 0.714

Asia WGS AF: 0.787 AC: 2735 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.8
DANN	Benign	0.55
PhyloP100		-0.41
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: rs4145993; hg19: chr4-95916279;