rs35572415

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_004329.3(BMPR1A):c.1140C>T(p.Asp380Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0188 in 1,613,362 control chromosomes in the GnomAD database, including 347 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 24 hom., cov: 32)

Exomes 𝑓: 0.019 ( 323 hom. )

Consequence

BMPR1A
NM_004329.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:19

Conservation

PhyloP100: 1.03

Publications

12 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.31).

BP6

Variant 10-86919443-C-T is Benign according to our data. Variant chr10-86919443-C-T is described in ClinVar as Benign. ClinVar VariationId is 132691.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.03 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.015 (2285/152250) while in subpopulation AMR AF = 0.0242 (371/15302). AF 95% confidence interval is 0.0222. There are 24 homozygotes in GnomAd4. There are 1086 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 2285 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMPR1A	NM_004329.3 link	c.1140C>T	p.Asp380Asp	synonymous_variant	Exon 10 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.1140C>T	p.Asp380Asp	synonymous_variant	Exon 10 of 13	1	NM_004329.3	ENSP00000361107.2		P36894

Frequencies

GnomAD3 genomes

AF:

0.0150

AC:

2287

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00408

Gnomad AMI

AF:

0.0230

Gnomad AMR

AF:

0.0243

Gnomad ASJ

AF:

0.0153

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00539

Gnomad FIN

AF:

0.00584

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0224

Gnomad OTH

AF:

0.0249

GnomAD2 exomes

AF:

0.0146

AC:

3665

AN:

251006

AF XY:

0.0152

show subpopulations

Gnomad AFR exome

AF:

0.00369

Gnomad AMR exome

AF:

0.0141

Gnomad ASJ exome

AF:

0.0144

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00614

Gnomad NFE exome

AF:

0.0219

Gnomad OTH exome

AF:

0.0173

GnomAD4 exome

AF:

0.0192

AC:

27985

AN:

1461112

Hom.:

323

Cov.:

AF XY:

0.0189

AC XY:

13731

AN XY:

726878

show subpopulations

African (AFR)

AF:

0.00314

AC:

105

AN:

33454

American (AMR)

AF:

0.0158

AC:

708

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0136

AC:

355

AN:

26132

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39700

South Asian (SAS)

AF:

0.00779

AC:

672

AN:

86230

European-Finnish (FIN)

AF:

0.00642

AC:

343

AN:

53420

Middle Eastern (MID)

AF:

0.0321

AC:

171

AN:

5320

European-Non Finnish (NFE)

AF:

0.0221

AC:

24553

AN:

1111816

Other (OTH)

AF:

0.0178

AC:

1075

AN:

60324

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

1583

3165

4748

6330

7913

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

892

1784

2676

3568

4460

<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:

0.0150

AC:

2285

AN:

152250

Hom.:

Cov.:

AF XY:

0.0146

AC XY:

1086

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.00407

AC:

169

AN:

41552

American (AMR)

AF:

0.0242

AC:

371

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0153

AC:

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5180

South Asian (SAS)

AF:

0.00539

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00584

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0224

AC:

1524

AN:

67994

Other (OTH)

AF:

0.0246

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

120

240

359

479

599

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.0169

Hom.:

Bravo

AF:

0.0168

Asia WGS

AF:

0.00577

AC:

AN:

3478

EpiCase

AF:

0.0248

EpiControl

AF:

0.0248

ClinVar

Significance: Benign

Submissions summary: Benign:19

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

Aug 14, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

The BMPR1A p.Asp380= variant was identified in 1 of 96 proband chromosomes (frequency: 0.01) from one individual with Hereditary hemorrhagic telangiectasia; however, the variant is identified as a polymorphism (Lesca 2006). The variant was also identified in the following databases: dbSNP (ID: rs35572415) as "With Likely benign allele", ClinVar (5x benign, 1x likely benign), Clinvitae, and LOVD 3.0 (4x). The variant was not identified in Cosmic or the MutDB database. The variant was identified in control databases in 3968 of 276746 chromosomes (34 homozygous) at a frequency of 0.01 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 92 of 24020 chromosomes (freq: 0.004), Other in 129 of 6460 chromosomes (freq: 0.02), Latino in 477 of 34416 chromosomes (freq: 0.01), European in 2719 of 126260 chromosomes (freq: 0.02), Ashkenazi Jewish in 149 of 10150 chromosomes (freq: 0.01), Finnish in 154 of 25792 chromosomes (freq: 0.006), and South Asian in 248 of 30782 chromosomes (freq: 0.008). The variant was not observed in the East Asian population. A study by Pyatt 2006 investigating Juvenile polyposis syndrome listed this variant as a polymorphism. The p.Asp380= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

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

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 12, 2016

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:4

Feb 20, 2018

True Health Diagnostics

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 09, 2016

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 21, 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. -

Jan 20, 2025

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The synonymous variant NM_004329.3(BMPR1A):c.1140C>T (p.Asp380=) has been reported to ClinVar as Benign with a status of (2 stars) criteria provided, multiple submitters, no conflicts (Variation ID 132691 as of 2025-01-02). The variant is observed in one or more well-documented healthy adults. The p.Asp380= variant is not predicted to disrupt an existing splice site. The p.Asp380= variant results in a substitution of a base that is not predicted conserved by GERP++ and PhyloP. For these reasons, this variant has been classified as Benign -

not provided

Benign:3

Nov 11, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Juvenile polyposis syndrome

Benign:3

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 06, 2024

Myriad Genetics, Inc.

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Generalized juvenile polyposis/juvenile polyposis coli

Benign:1

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

BayesDel_noAF

Benign

-0.31

CADD

Benign

7.7

(source)

DANN

Benign

0.52

PhyloP100

1.0

Mutation Taster

=94/6

polymorphism

(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