rs140592056

Variant names:

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PP2PP3BP4_StrongBP6BS1BS2

The NM_004329.3(BMPR1A):c.1243G>A(p.Glu415Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000493 in 1,614,142 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00055 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00049 ( 3 hom. )

Consequence

BMPR1A
NM_004329.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:20O:1

Conservation

PhyloP100: 9.93

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 -11 ACMG points.

PP2

Missense variant in the BMPR1A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 17 curated pathogenic missense variants (we use a threshold of 10). The gene has 19 curated benign missense variants. Gene score misZ: 1.9176 (below the threshold of 3.09). Trascript score misZ: 3.8989 (above the threshold of 3.09). GenCC associations: The gene is linked to polyposis syndrome, hereditary mixed, 2, generalized juvenile polyposis/juvenile polyposis coli, hereditary mixed polyposis syndrome, pulmonary arterial hypertension, juvenile polyposis syndrome.

PP3

Multiple lines of computational evidence support a deleterious effect 8: BayesDel_addAF, BayesDel_noAF, Cadd, Dann, Eigen, phyloP100way_vertebrate, PrimateAI, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationAssessor, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.03156662).

BP6

Variant 10-86921596-G-A is Benign according to our data. Variant chr10-86921596-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 41779.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=11, Benign=6, Uncertain_significance=1, not_provided=1}.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000545 (83/152272) while in subpopulation AMR AF= 0.00072 (11/15286). AF 95% confidence interval is 0.000403. There are 2 homozygotes in gnomad4. There are 41 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 83 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMPR1A	NM_004329.3 link	c.1243G>A	p.Glu415Lys	missense_variant	Exon 11 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.1243G>A	p.Glu415Lys	missense_variant	Exon 11 of 13	1	NM_004329.3	ENSP00000361107.2		P36894

Frequencies

GnomAD3 genomes

AF:

0.000545

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000721

Gnomad ASJ

AF:

0.0159

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000887

AC:

223

AN:

251480

Hom.:

AF XY:

0.000898

AC XY:

122

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000318

Gnomad ASJ exome

AF:

0.0165

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000299

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.000487

AC:

712

AN:

1461870

Hom.:

Cov.:

AF XY:

0.000506

AC XY:

368

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000470

Gnomad4 ASJ exome

AF:

0.0160

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000147

Gnomad4 OTH exome

AF:

0.00142

GnomAD4 genome

AF:

0.000545

AC:

AN:

152272

Hom.:

Cov.:

AF XY:

0.000551

AC XY:

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000720

Gnomad4 ASJ

AF:

0.0159

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.00235

Hom.:

Bravo

AF:

0.000661

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000684

AC:

EpiCase

AF:

0.000600

EpiControl

AF:

0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:20Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:7

Jul 13, 2012

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Sep 02, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The BMPR1A c.1243G>A (p.Glu415Lys) variant involves the alteration of a conserved nucleotide. Glu415Lys occurs at a position that is conserved across mammals and is located in the protein kinase domain, and 4/5 in silico tools predict a damaging outcome for this variant. This variant was found in 87/122544 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0011238 (75/66740). This frequency is about 562 times the estimated maximal expected allele frequency of a pathogenic BMPR1A variant (0.000002), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. This variant was also observed in three individuals with a history of moderate-load polyposis; reported pathology included hyperplastic, hamartomatous, juvenile and adenomatous polyps (Ngeow 2013); and in one individual undergoing hereditary panel testing for a personal and/or family history suspicious for Lynch syndrome (Yurgelun 2015). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance or likely benign. Taken together and based on the prevalence in the general population, this variant is classified as benign. -

May 03, 2020

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 14, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 30, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 27621404, 25722345, 27878467, 24728327, 25637381, 25980754, 22703879, 23399955, 25801821, 27153395, 27884173, 24448499, 30680046) -

Jan 24, 2018

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BMPR1A: PP3, BS1, BS2 -

Dec 27, 2017

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Uncertain:1Benign:2Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2020

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 31, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant is present in HGMD in 5 papers, with comments suggesting likely benign. The variant is present in ExAC at a Max MAF of 0.11% and at 1.6% (165) of Ashkenazi alleles in gnomAD - frequency too high for disease. It is classified as Likely Benign by 4 submitters (GeneDx, Invitae, Ambry, CSER_CC_NCGL) and as VUS by Biesecker lab. -

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Hereditary cancer-predisposing syndrome

Benign:4

Sep 13, 2017

True Health Diagnostics

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 28, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Oct 31, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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. -

May 19, 2016

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Generalized juvenile polyposis/juvenile polyposis coli

Benign:3

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Mar 12, 2018

Counsyl

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Juvenile polyposis syndrome

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 02, 2023

Myriad Genetics, Inc.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign. Homozygosity has been confirmed in one or more individuals. As homozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality, this variant is unlikely to be pathogenic. -

Sep 27, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malignant tumor of breast

Uncertain:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

BMPR1A, EXON11, c.1243G>A, p.Glu415Lys, Heterozygous, Uncertain SignificancernThe BMPR1A p.Glu415Lys variant was identified in 15 of 11178 proband chromosomes (frequency: 0.001) from individuals or families with breast cancer, Lynch Syndrome, or undefined moderate load gastrointestinal polyposis and was present in 2 of 1362 control chromosomes (frequency: 0.002) from healthy individuals (Balmana 2016, Ngeow 2013, Tung 2015, Yurgelun 2015, Bodian 2014). The variant was also identified in dbSNP (ID: rs140592056) as "With other allele", ClinVar (classified as benign by Invitae and Integrated Genetics/Laboratory Corporation of America; as likely benign by GeneDx, Ambry Genetics, PreventionGenetics, and six other submitters; and as uncertain significance by two submitters), and LOVD 3.0 (1x as VUS). The variant was identified in control databases in 221 of 277220 chromosomes (1 homozygous) at a frequency of 0.0008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 161 of 10152 chromosomes (freq: 0.02, increasing the likelihood this could be a low frequency benign variant), African in 1 of 24028 chromosomes (freq: 0.00004), Other in 7 of 6466 chromosomes (freq: 0.001), Latino in 10 of 34420 chromosomes (freq: 0.0003), European in 39 of 126714 chromosomes (freq: 0.0003), East Asian in 1 of 18870 chromosomes (freq: 0.00005), and South Asian in 2 of 30782 chromosomes (freq: 0.00006); it was not observed in the Finnish population. The p.Glu415 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.rnAssessment Date: 2019/07/23rnReferences (PMIDs): 27621404, 23399955, 25186627, 25980754, 24728327 -

Gastrointestinal polyposis

Benign:1

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.71

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

0.99

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.032

MetaSVM

Pathogenic

0.84

MutationAssessor

Benign

1.1

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-3.3

REVEL

Pathogenic

0.81

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0050

Polyphen

1.0

Vest4

0.92

MVP

0.96

MPC

0.96

ClinPred

0.074

GERP RS

5.6

Varity_R

0.77

gMVP

0.74

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