rs730881436

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PP2PP3_StrongBS2

The ENST00000372037.8(BMPR1A):c.1082G>A(p.Arg361Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,460,618 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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. R361G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

BMPR1A
ENST00000372037.8 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 10.0

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.994

BS2

High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BMPR1A	NM_004329.3 linkuse as main transcript	c.1082G>A	p.Arg361Gln	missense_variant	10/13	ENST00000372037.8	NP_004320.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BMPR1A	ENST00000372037.8 linkuse as main transcript	c.1082G>A	p.Arg361Gln	missense_variant	10/13	1	NM_004329.3	ENSP00000361107	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1460618

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

726654

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:

0.0000232

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000936

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 20, 2024	The p.R361Q variant (also known as c.1082G>A), located in coding exon 8 of the BMPR1A gene, results from a G to A substitution at nucleotide position 1082. The arginine at codon 361 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 12, 2021	This missense variant replaces arginine with glutamine at codon 361 of the BMPR1A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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	curation	Sema4, Sema4	Jun 23, 2021	- -

Polyposis syndrome, hereditary mixed, 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jul 14, 2023

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 16, 2015

This variant is denoted BMPR1A c.1082G>A at the cDNA level, p.Arg361Gln (R361Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGA>CAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BMPR1A Arg361Gln was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Arginine and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. BMPR1A Arg361Gln occurs at a position that is conserved across species and is located in the protein kinase domain (Howe 2004). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether BMPR1A Arg361Gln is pathogenic or benign. We consider it to be a variant of uncertain significance. -

Juvenile polyposis syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 29, 2023

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 361 of the BMPR1A protein (p.Arg361Gln). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BMPR1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 182070). 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. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.93

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.94

FATHMM_MKL

Pathogenic

0.99

M_CAP

Pathogenic

0.71

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.1

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.91

PROVEAN

Uncertain

-4.0

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.99

MutPred

0.99

Loss of MoRF binding (P = 0.0613);

MVP

1.0

MPC

2.8

ClinPred

1.0

GERP RS

4.9

Varity_R

0.96

gMVP

0.87

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