rs11528010

Positions:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as 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:16O:1

Conservation

PhyloP100: 3.20

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), BMPR1A. . Gene score misZ 1.9176 (greater than the threshold 3.09). Trascript score misZ 3.8989 (greater than threshold 3.09). GenCC has associacion of gene with polyposis syndrome, hereditary mixed, 2, generalized juvenile polyposis/juvenile polyposis coli, hereditary mixed polyposis syndrome, pulmonary arterial hypertension, juvenile polyposis syndrome.

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 id is 41782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86876022-C-A is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
BMPR1A	NM_004329.3 linkuse as main transcript	c.4C>A	p.Pro2Thr	missense_variant	3/13	ENST00000372037.8	NP_004320.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BMPR1A	ENST00000372037.8 linkuse as main transcript	c.4C>A	p.Pro2Thr	missense_variant	3/13	1	NM_004329.3	ENSP00000361107	P1

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

GnomAD3 exomes

AF:

0.358

AC:

89783

AN:

251114

Hom.:

18858

AF XY:

0.343

AC XY:

46507

AN XY:

135738

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 SAS exome

AF:

0.300

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

Gnomad4 AFR exome

AF:

0.679

Gnomad4 AMR exome

AF:

0.385

Gnomad4 ASJ exome

AF:

0.379

Gnomad4 EAS exome

AF:

0.717

Gnomad4 SAS exome

AF:

0.300

Gnomad4 FIN exome

AF:

0.362

Gnomad4 NFE exome

AF:

0.245

Gnomad4 OTH exome

AF:

0.322

GnomAD4 genome

AF:

0.404

AC:

61474

AN:

152024

Hom.:

15021

Cov.:

AF XY:

0.408

AC XY:

30351

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.660

Gnomad4 AMR

AF:

0.349

Gnomad4 ASJ

AF:

0.396

Gnomad4 EAS

AF:

0.703

Gnomad4 SAS

AF:

0.315

Gnomad4 FIN

AF:

0.376

Gnomad4 NFE

AF:

0.252

Gnomad4 OTH

AF:

0.390

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:16Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5Other:1

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided

Uncertain:1Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 24728327) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -

Juvenile polyposis syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Hereditary cancer-predisposing syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 09, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 19, 2014	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

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

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

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;.

MutationTaster

Benign

1.0

P;P

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

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