rs1057517610

chr10-86890164-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PP2 PP3

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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P57S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: BMPR1A NM_004329.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 5.64

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a topological_domain Extracellular (size 128) in uniprot entity BMR1A_HUMAN there are 20 pathogenic changes around while only 2 benign (91%) in NM_004329.3
• PP2: Missense variant where missense usually causes diseases, BMPR1A
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.788

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BMPR1A	NM_004329.3	c.170C>G	p.Pro57Arg	missense_variant	4/13	ENST00000372037.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMPR1A	ENST00000372037.8	c.170C>G	p.Pro57Arg	missense_variant	4/13	1	NM_004329.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251386 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135858

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: 9 AN: 1461820 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727216

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.: 32

Bravo AF: 0.00000756

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Juvenile polyposis syndrome Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 02, 2024	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 02, 2023	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 28, 2023	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. -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 07, 2023	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 15, 2023	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 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; however, arginine is the reference amino acid in other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 03, 2022

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) -

Generalized juvenile polyposis/juvenile polyposis coli Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Oct 11, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
Cadd	Benign	20
Dann	Benign	0.93
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.028
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Benign	0.021	T
MetaRNN	Pathogenic	0.79	D
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	0.63	N
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	0.010	N
REVEL	Uncertain	0.36
Sift	Benign	0.50	T
Sift4G	Benign	0.70	T
Polyphen		0.0010	B
Vest4		0.75
MutPred		0.77		Gain of sheet (P = 0.039);
MVP		0.83
MPC		0.43
ClinPred		0.36	T
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

Other links and lift over

dbSNP: rs1057517610; hg19: chr10-88649921;