Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2PM5PP3_StrongPP5_Moderate

The NM_001203.3(BMPR1B):c.1457G>A(p.Arg486Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R486W) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

BMPR1B
NM_001203.3 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 9.60

Publications

10 publications found

Variant links:

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

BMPR1B links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr4-95154620-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 6556.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.953

PP5

Variant 4-95154621-G-A is Pathogenic according to our data. Variant chr4-95154621-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 6558.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001203.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
BMPR1B	NM_001203.3	MANE Select	c.1457G>A	p.Arg486Gln	missense	Exon 13 of 13	NP_001194.1
BMPR1B	NM_001256793.2		c.1547G>A	p.Arg516Gln	missense	Exon 11 of 11	NP_001243722.1
BMPR1B	NM_001256792.2		c.1457G>A	p.Arg486Gln	missense	Exon 11 of 11	NP_001243721.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
BMPR1B	ENST00000515059.6	TSL:1 MANE Select	c.1457G>A	p.Arg486Gln	missense	Exon 13 of 13	ENSP00000426617.1
BMPR1B	ENST00000394931.1	TSL:1	c.1457G>A	p.Arg486Gln	missense	Exon 10 of 10	ENSP00000378389.1
BMPR1B	ENST00000512312.5	TSL:1	c.1457G>A	p.Arg486Gln	missense	Exon 11 of 11	ENSP00000425444.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.000131

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Likely pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

BMPR1B-related disorder (1)

Type A2 brachydactyly (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.78

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.95

MetaSVM

Uncertain

0.75

MutationAssessor

Benign

0.73

PhyloP100

9.6

PrimateAI

Pathogenic

0.90

PROVEAN

Uncertain

-3.8

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.75

MutPred

0.90

Loss of MoRF binding (P = 0.0521)

MVP

0.98

MPC

0.29

ClinPred

0.99

GERP RS

5.9

Varity_R

0.94

gMVP

0.77

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over