rs113849804

Positions:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2BP4BP6BS1BS2

The NM_004329.3(BMPR1A):c.1433G>A(p.Arg478His) variant causes a missense change. The variant allele was found at a frequency of 0.000354 in 1,614,098 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00037 ( 0 hom. )

Consequence

BMPR1A
NM_004329.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9B:8O:1

Conservation

PhyloP100: 5.94

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:

BMPR1A (HGNC:):

BMPR1A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 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=0.3115873).

BP6

Variant 10-86923466-G-A is Benign according to our data. Variant chr10-86923466-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 41780.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Uncertain_significance=7, not_provided=1, Benign=1}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000237 (36/152204) while in subpopulation NFE AF= 0.000456 (31/68032). AF 95% confidence interval is 0.000329. There are 0 homozygotes in gnomad4. There are 13 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 36 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BMPR1A	NM_004329.3 linkuse as main transcript	c.1433G>A	p.Arg478His	missense_variant	12/13	ENST00000372037.8	NP_004320.2	P36894

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BMPR1A	ENST00000372037.8 linkuse as main transcript	c.1433G>A	p.Arg478His	missense_variant	12/13	1	NM_004329.3	ENSP00000361107.2		P36894

Frequencies

GnomAD3 genomes

AF:

0.000237

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000456

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000171

AC:

AN:

251494

Hom.:

AF XY:

0.000177

AC XY:

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000290

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000367

AC:

536

AN:

1461894

Hom.:

Cov.:

AF XY:

0.000352

AC XY:

256

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000268

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000437

Gnomad4 OTH exome

AF:

0.000613

GnomAD4 genome

AF:

0.000237

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000456

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000162

Hom.:

Bravo

AF:

0.000280

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000140

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9Benign:8Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4Benign:1Other:1

Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 24, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 21, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed individuals with breast cancer, colorectal cancer, or other Lynch syndrome-associated tumor (Tung et al., 2015; Yurgelun et al., 2015; DeRycke et al., 2017; Pearlman et al., 2017; Yurgelun et al., 2017; MacFarland et al., 2021); This variant is associated with the following publications: (PMID: 22703879, 28135145, 30374176, 33097490, 25186627, 25980754, 28944238, 27978560, 32522605, 33032550, 25996639, 28873162, 25801821, 30814609) -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpretted as Uncertain significance and reported on 06-21-2018 by Lab or GTR ID 26957. 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. -
Uncertain significance, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 17, 2023	BS1 -

not specified

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 28, 2016	The p.Arg478His variant in BMPR1A has been reported in 1 individual with suspect ed Lynch Syndrome (Yurgelun 2015), 2 individuals who underwent exome sequencing for non-cancer related indications (Johnston 2012, D'Alessandro 2016) and has al so been reported in ClinVar (Variation ID 41780). This variant has also been ide ntified in 15/66738 of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs113849804). Computational predict ion tools and conservation analysis suggest that the p.Arg478His variant may not impact the protein, though this information is not predictive enough to rule ou t pathogenicity. In summary, the clinical significance of the p.Arg478His varian t is uncertain. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 28, 2024	Variant summary: BMPR1A c.1433G>A (p.Arg478His) results in a non-conservative amino acid change located in the Serine-threonine/tyrosine-protein kinase, catalytic domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00017 in 251494 control chromosomes, predominantly at a frequency of 0.00029 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 145 fold of the estimated maximal expected allele frequency for a pathogenic variant in BMPR1A causing Juvenile Polyposis Syndrome phenotype (2e-06). Although c.1433G>A has been reported in the literature within settings of multigene panel testing for hereditary cancers, these report(s) do not provide unequivocal conclusions about association of the variant with Juvenile Polyposis Syndrome (example Yurgelun_2015, Dalessandro_2015, Johnston_2012, Pearlman_2016, Tung_2014, Yurgelun_2017, Tsai_2019). A recent study reporting outcomes of re-classification of VUS from patient-driven family studies reported this variant with no cases of polyposis in a family (Tsai_2019). Co-occurrences with other pathogenic variant(s) have been reported in the literature and at our laboratory (examples, Yurgelun_2015, EPCAM deletion of exons 1-9; Our laboratory, BRCA2 c.1813dupA, p.I1605fs*11; Tsai_2019, an unspecified co-occurrence with a pathogenic variant in the PALB2 gene), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22703879, 25980754, 25186627, 25996639, 27978560, 28135145, 30374176). ClinVar contains an entry for this variant (Variation ID: 41780). Based on the evidence outlined above, the variant was classified as likely benign. -

Hereditary cancer-predisposing syndrome

Benign:3

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Oct 25, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 28, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 25, 2021	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

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	research	University of Washington Department of Laboratory Medicine, University of Washington	Apr 30, 2018	The BMPR1A variant designated as NM_004329.2:c.1433G>A (p.Arg478His) is classified as likely benign. This variant is listed in population databases and is found in approximately 1 out of 1750 individuals of European ancestry. In silico programs predict that this variant is likely to be tolerated (SIFT, Polyphen-2, Align-GVGD). In one observed family, this variant was not shown to segregate with colon polyps in family members who were over 60 years old. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives approimately 1% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter BMPR1A function or modify cancer risk. A modest (less than 2 fold) increase in cancer risk due to this variant cannot be entirely excluded. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Apr 05, 2018	- -

Juvenile polyposis syndrome

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 02, 2023	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. -

Polyposis syndrome, hereditary mixed, 2;C1868081:Generalized juvenile polyposis/juvenile polyposis coli

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 23, 2017

- -

BMPR1A-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 03, 2024

The BMPR1A c.1433G>A variant is predicted to result in the amino acid substitution p.Arg478His. This variant has been identified in an individual from a study of participants who were selected for a range of atherosclerosis phenotypes, but not for a personal or family history of cancer (Johnston et al. 2012. PubMed ID: 22703879). Additionally, it was identified in an individual with atrioventricular septum defect who also had learning and psychiatric disabilities and cervical spine anomalies (D'Alessandro et al. 2016. PubMed ID: 25996639). Multiple studies identified this variant in individuals with colorectal cancer and classified it as a variant of uncertain significance (Table S2, Yurgelun et al. 2015. PubMed ID: 25980754; eTable 2, Pearlman et al. 2017. PubMed ID: 27978560). This variant is reported in 0.029% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations ranging from benign to uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/41780/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.15

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.75

Eigen

Benign

0.087

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.97

M_CAP

Benign

0.058

MetaRNN

Benign

0.31

MetaSVM

Uncertain

0.34

MutationAssessor

Benign

1.7

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-2.9

REVEL

Uncertain

0.38

Sift

Uncertain

0.020

Sift4G

Uncertain

0.056

Polyphen

0.15

Vest4

0.40

MVP

0.85

MPC

0.72

ClinPred

0.093

GERP RS

4.6

Varity_R

0.32

gMVP

0.66

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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