rs11528010

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004329.3(BMPR1A):c.4C>A(p.Pro2Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.297 in 1,592,936 control chromosomes in the GnomAD database, including 83,045 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P2L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.40 ( 15021 hom., cov: 32)

Exomes 𝑓: 0.29 ( 68024 hom. )

Consequence

BMPR1A
NM_004329.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:1B:17O:1

Conservation

PhyloP100: 3.20

Publications

54 publications found

Variant links:

Genes affected

BMPR1A (HGNC:1076): (bone morphogenetic protein receptor type 1A) The bone morphogenetic protein (BMP) receptors are a family of transmembrane serine/threonine kinases that include the type I receptors BMPR1A and BMPR1B and the type II receptor BMPR2. These receptors are also closely related to the activin receptors, ACVR1 and ACVR2. The ligands of these receptors are members of the TGF-beta superfamily. TGF-betas and activins transduce their signals through the formation of heteromeric complexes with 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. [provided by RefSeq, Jul 2008]

BMPR1A Gene-Disease associations (from GenCC):

generalized juvenile polyposis/juvenile polyposis coli
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Genomics England PanelApp
juvenile polyposis syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P
polyposis syndrome, hereditary mixed, 2
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
hereditary mixed polyposis syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
congenital heart defects, multiple types
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
pulmonary arterial hypertension
Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

BMPR1A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=3.1856E-6).

BP6

Variant 10-86876022-C-A is Benign according to our data. Variant chr10-86876022-C-A is described in ClinVar as Benign. ClinVar VariationId is 41782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.684 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMPR1A	NM_004329.3 link	c.4C>A	p.Pro2Thr	missense_variant	Exon 3 of 13	ENST00000372037.8	NP_004320.2	P36894

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMPR1A	ENST00000372037.8 link	c.4C>A	p.Pro2Thr	missense_variant	Exon 3 of 13	1	NM_004329.3	ENSP00000361107.2		P36894

Frequencies

GnomAD3 genomes

AF:

0.404

AC:

61375

AN:

151904

Hom.:

14968

Cov.:

show subpopulations

Gnomad AFR

AF:

0.660

Gnomad AMI

AF:

0.240

Gnomad AMR

AF:

0.349

Gnomad ASJ

AF:

0.396

Gnomad EAS

AF:

0.703

Gnomad SAS

AF:

0.315

Gnomad FIN

AF:

0.376

Gnomad MID

AF:

0.354

Gnomad NFE

AF:

0.252

Gnomad OTH

AF:

0.389

GnomAD2 exomes

AF:

0.358

AC:

89783

AN:

251114

AF XY:

0.343

show subpopulations

Gnomad AFR exome

AF:

0.668

Gnomad AMR exome

AF:

0.390

Gnomad ASJ exome

AF:

0.376

Gnomad EAS exome

AF:

0.718

Gnomad FIN exome

AF:

0.371

Gnomad NFE exome

AF:

0.258

Gnomad OTH exome

AF:

0.317

GnomAD4 exome

AF:

0.286

AC:

411907

AN:

1440912

Hom.:

68024

Cov.:

AF XY:

0.285

AC XY:

204519

AN XY:

717892

show subpopulations

African (AFR)

AF:

0.679

AC:

22134

AN:

32594

American (AMR)

AF:

0.385

AC:

17206

AN:

44648

Ashkenazi Jewish (ASJ)

AF:

0.379

AC:

9840

AN:

25972

East Asian (EAS)

AF:

0.717

AC:

28300

AN:

39448

South Asian (SAS)

AF:

0.300

AC:

25686

AN:

85746

European-Finnish (FIN)

AF:

0.362

AC:

19300

AN:

53312

Middle Eastern (MID)

AF:

0.353

AC:

1888

AN:

5356

European-Non Finnish (NFE)

AF:

0.245

AC:

268360

AN:

1094224

Other (OTH)

AF:

0.322

AC:

19193

AN:

59612

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.410

Heterozygous variant carriers

12912

25824

38736

51648

64560

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9366

18732

28098

37464

46830

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.404

AC:

61474

AN:

152024

Hom.:

15021

Cov.:

AF XY:

0.408

AC XY:

30351

AN XY:

74304

show subpopulations

African (AFR)

AF:

0.660

AC:

27377

AN:

41472

American (AMR)

AF:

0.349

AC:

5327

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.396

AC:

1375

AN:

3468

East Asian (EAS)

AF:

0.703

AC:

3634

AN:

5166

South Asian (SAS)

AF:

0.315

AC:

1516

AN:

4818

European-Finnish (FIN)

AF:

0.376

AC:

3966

AN:

10544

Middle Eastern (MID)

AF:

0.370

AC:

108

AN:

292

European-Non Finnish (NFE)

AF:

0.252

AC:

17128

AN:

67966

Other (OTH)

AF:

0.390

AC:

825

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1616

3232

4848

6464

8080

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

542

1084

1626

2168

2710

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.325

Hom.:

4121

Bravo

AF:

0.421

TwinsUK

AF:

0.237

AC:

877

ALSPAC

AF:

0.249

AC:

961

ESP6500AA

AF:

0.650

AC:

2863

ESP6500EA

AF:

0.256

AC:

2203

ExAC

AF:

0.356

AC:

43215

EpiCase

AF:

0.262

EpiControl

AF:

0.260

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:17Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5Other:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Uncertain:1Benign:4

Jul 13, 2012

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:research

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 24728327) -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Juvenile polyposis syndrome

Benign:4

Oct 03, 2024

All of Us Research Program, National Institutes of Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 30, 2024

Myriad Genetics, Inc.

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:2

Mar 09, 2016

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 19, 2014

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Generalized juvenile polyposis/juvenile polyposis coli

Benign:2

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Benign

0.077

DEOGEN2

Benign

0.15

T;.

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.49

FATHMM_MKL

Benign

0.023

LIST_S2

Benign

0.23

.;T

MetaRNN

Benign

0.0000032

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.81

N;.

PhyloP100

3.2

PrimateAI

Uncertain

0.49

PROVEAN

Benign

0.31

N;.

REVEL

Benign

0.21

Sift

Benign

1.0

T;.

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;.

Vest4

0.053

MPC

0.44

ClinPred

0.0044

GERP RS

5.3

Varity_R

0.033

gMVP

0.37

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over