rs1057517610

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PP2PP3BS2

The NM_004329.3(BMPR1A):c.170C>G(p.Pro57Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000616 in 1,461,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

BMPR1A
NM_004329.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:9

Conservation

PhyloP100: 5.64

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 Uncertain_significance. Variant got 0 ACMG points.

PM1

In a topological_domain Extracellular (size 128) in uniprot entity BMR1A_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_004329.3

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

MetaRNN computational evidence supports a deleterious effect, 0.788

BS2

High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMPR1A	NM_004329.3 link	c.170C>G	p.Pro57Arg	missense_variant	Exon 4 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.170C>G	p.Pro57Arg	missense_variant	Exon 4 of 13	1	NM_004329.3	ENSP00000361107.2		P36894

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251386

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135858

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461820

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000809

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Juvenile polyposis syndrome

Uncertain:3

Aug 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 57 of the BMPR1A protein (p.Pro57Arg). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individuals with juvenile polyposis (PMID: 14734220, 15235019, 18823382). ClinVar contains an entry for this variant (Variation ID: 371995). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is not expected to disrupt BMPR1A function with a negative predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on BMPR1A function (PMID: 23433720). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Mar 02, 2023

Myriad Genetics, Inc.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -

Nov 28, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces proline with arginine at codon 57 of the BMPR1A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. A functional study reported abnormal subcellular localization of the variant but higher than wild-type level of BMP signaling activity in transfected cell cultures (PMID: 23433720). This variant has been reported in at least one individual affected with sporadic juvenile polyposis (PMID: 15235019, 18823382) and one family affected with juvenile polyposis, including multiple cases of polyposis and two cases of colon cancer (PMID: 14734220). This variant has been identified in 1/251386 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not provided

Uncertain:2

Oct 03, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies are inconclusive: protein expression levels comparable to wild type, increased BMP signaling, and abnormal cellular localization (Howe et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 15235019, 18823382, Attard2004[abstract], 33032550, 23433720, 14734220) -

Mar 13, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BMPR1A c.170C>G (p.Pro57Arg) variant has been reported in the published literature in affected individuals with juvenile polyposis syndrome (JPS) (PMIDs: 14734220 (2004), 15235019 (2004), and 18823382 (2009)). A functional study found that this variant had an inconclusive impact on protein function (PMID: 23433720 (2013)). The frequency of this variant in the general population, 0.000004 (1/251386 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Hereditary cancer-predisposing syndrome

Uncertain:2

Apr 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P57R variant (also known as c.170C>G), located in coding exon 2 of the BMPR1A gene, results from a C to G substitution at nucleotide position 170. The proline at codon 57 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been reported in several individuals diagnosed with juvenile polyposis syndrome (JPS) (Lynch HT et al. Cancer Genet. Cytogenet., 2004 Jan;148:104-17; Howe JR et al. J. Med. Genet., 2004 Jul;41:484-91; Calva-Cerqueira D et al. Clin. Genet., 2009 Jan;75:79-85; Ambry internal data). However, this variant has been detected in multiple individuals with no reported features of JPS (Ambry internal data). In a functional study, subcellular localization was affected with the majority of protein showing intracellular localization as opposed to wild type BMPR1A, which localized solely to the membrane; however, bone morphogenetic protein signaling measured by a reporter assay was not reduced for BMPR1A p.P57R compared to wild type. (Howe JR et al. J. Surg. Res., 2013 Oct;184:739-45). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Sep 07, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces proline with arginine at codon 57 of the BMPR1A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study reported no decrease in protein expression or bone morphogenetic protein signaling activity, but abnormal sub-cellular localization, compared to wild-type in transfected cell cultures (PMID: 23433720). This variant has been reported in individuals affected with juvenile polyposis syndrome (PMID: 14734220, 15235019, 18823382; ClinVar SCV000581497.6), and in one family with multiple members affected with polyposis and/or colon cancer (PMID: 14734220). This variant has been identified in 1/251386 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Generalized juvenile polyposis/juvenile polyposis coli

Uncertain:1

Oct 11, 2016

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Juvenile polyposis syndrome;C1864730:Polyposis syndrome, hereditary mixed, 2

Uncertain:1

Feb 21, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Uncertain

0.0

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.11

Eigen

Benign

-0.028

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.90

M_CAP

Benign

0.021

MetaRNN

Pathogenic

0.79

MetaSVM

Benign

-0.64

MutationAssessor

Benign

0.63

PrimateAI

Uncertain

0.65

PROVEAN

Benign

0.010

REVEL

Uncertain

0.36

Sift

Benign

0.50

Sift4G

Benign

0.70

Polyphen

0.0010

Vest4

0.75

MutPred

0.77

Gain of sheet (P = 0.039);

MVP

0.83

MPC

0.43

ClinPred

0.36

GERP RS

6.0

Varity_R

0.49

gMVP

0.93

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