rs34970181

Positions:

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_ModerateBP6_Very_StrongBS1

The NM_001203.3(BMPR1B):c.1112G>A(p.Arg371Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000933 in 1,613,874 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00086 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00094 ( 1 hom. )

Consequence

BMPR1B
NM_001203.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts U:1B:2O:1

Conservation

PhyloP100: 8.00

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.13577956).

BP6

Variant 4-95148783-G-A is Benign according to our data. Variant chr4-95148783-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 441001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000861 (131/152138) while in subpopulation SAS AF= 0.00187 (9/4816). AF 95% confidence interval is 0.000975. There are 0 homozygotes in gnomad4. There are 69 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BMPR1B	NM_001203.3 linkuse as main transcript	c.1112G>A	p.Arg371Gln	missense_variant	11/13	ENST00000515059.6	NP_001194.1	O00238-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BMPR1B	ENST00000515059.6 linkuse as main transcript	c.1112G>A	p.Arg371Gln	missense_variant	11/13	1	NM_001203.3	ENSP00000426617.1		O00238-1

Frequencies

GnomAD3 genomes

AF:

0.000862

AC:

131

AN:

152020

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000676

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000459

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00187

Gnomad FIN

AF:

0.000472

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00116

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.000994

AC:

250

AN:

251396

Hom.:

AF XY:

0.000935

AC XY:

127

AN XY:

135872

show subpopulations

Gnomad AFR exome

AF:

0.000677

Gnomad AMR exome

AF:

0.000955

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000544

Gnomad SAS exome

AF:

0.00134

Gnomad FIN exome

AF:

0.000554

Gnomad NFE exome

AF:

0.00120

Gnomad OTH exome

AF:

0.000978

GnomAD4 exome

AF:

0.000941

AC:

1375

AN:

1461736

Hom.:

Cov.:

AF XY:

0.000898

AC XY:

653

AN XY:

727166

show subpopulations

Gnomad4 AFR exome

AF:

0.000657

Gnomad4 AMR exome

AF:

0.000827

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.000428

Gnomad4 SAS exome

AF:

0.00145

Gnomad4 FIN exome

AF:

0.000431

Gnomad4 NFE exome

AF:

0.000986

Gnomad4 OTH exome

AF:

0.000878

GnomAD4 genome

AF:

0.000861

AC:

131

AN:

152138

Hom.:

Cov.:

AF XY:

0.000928

AC XY:

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.000674

Gnomad4 AMR

AF:

0.000459

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000387

Gnomad4 SAS

AF:

0.00187

Gnomad4 FIN

AF:

0.000472

Gnomad4 NFE

AF:

0.00116

Gnomad4 OTH

AF:

0.000475

Alfa

AF:

0.000936

Hom.:

Bravo

AF:

0.000808

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.00110

AC:

133

EpiCase

AF:

0.000873

EpiControl

AF:

0.000771

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1Benign:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

BMPR1B-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 28, 2024

The BMPR1B c.1112G>A variant is predicted to result in the amino acid substitution p.Arg371Gln. This variant was reported in an individual with pulmonary arterial hypertension (Supplementary Dataset 1 in Wang et al. 2018. PubMed ID: 30578397) and in a patient with cleft lip with/without cleft palate (Marini et al. 2019. PubMed ID: 31063268). This variant is reported in 0.13% of alleles in individuals of South Asian descent in gnomAD, including one homozygous individual. This variant has been interpreted by a single submitter in ClinVar as likely benign (https://preview.ncbi.nlm.nih.gov/clinvar/variation/441001/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Type A2 brachydactyly;C4225404:Acromesomelic dysplasia 3

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 26, 2024

- -

Type A2 brachydactyly

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

-0.040

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.79

D;D;.;D;D

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

.;.;D;.;D

M_CAP

Benign

0.049

MetaRNN

Benign

0.14

T;T;T;T;T

MetaSVM

Benign

-0.49

MutationAssessor

Benign

-0.070

N;N;.;N;N

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-3.9

D;D;D;D;D

REVEL

Uncertain

0.33

Sift

Uncertain

0.0010

D;D;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;D;D

Polyphen

1.0

D;D;.;D;D

Vest4

0.81

MVP

0.75

MPC

0.21

ClinPred

0.043

GERP RS

5.5

Varity_R

0.84

gMVP

0.85

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over