10-86912271-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBP6BS2

The NM_004329.3(BMPR1A):c.562C>T(p.Arg188Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,613,616 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

BMPR1A
NM_004329.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:3

Conservation

PhyloP100: 1.93

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 Likely_benign. Variant got -6 ACMG points.

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.26316845).

BP6

Variant 10-86912271-C-T is Benign according to our data. Variant chr10-86912271-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 246466.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=7}.

BS2

High AC in GnomAdExome4 at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMPR1A	NM_004329.3 link	c.562C>T	p.Arg188Cys	missense_variant	Exon 8 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.562C>T	p.Arg188Cys	missense_variant	Exon 8 of 13	1	NM_004329.3	ENSP00000361107.2		P36894

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152076

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251340

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135844

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000151

AC:

AN:

1461540

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727082

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:

0.00

Gnomad4 NFE exome

AF:

0.0000171

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152076

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74266

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:2

Apr 06, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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. -

May 30, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with cysteine at codon 188 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with BMPR1A-related disorders in the literature. This variant has been identified in 2/251340 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. -

May 17, 2016

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BMPR1A p.R188C, c.562 C>T variant did not segregate with colon cancer or polyposis in a single large family. Two individuals with no polyps did not have this BMPR1A variant and the majority of indivduals with multiple polyps or colon cancer did not have this variant. Based on this information, the likelihood that BMPR1A p.R188C is associated associated with polyposis is estimated to be less than one in one hundred. -

Juvenile polyposis syndrome

Uncertain:2

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 188 of the BMPR1A protein (p.Arg188Cys). This variant is present in population databases (no rsID available, gnomAD 0.002%). 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: 246466). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is not expected to disrupt BMPR1A function with a negative predictive value of 95%. 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. -

Apr 25, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Polyposis syndrome, hereditary mixed, 2

Uncertain:1

Oct 22, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

BMPR1A-related disorder

Uncertain:1

Aug 18, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BMPR1A c.562C>T variant is predicted to result in the amino acid substitution p.Arg188Cys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-88672028-C-T). A different variant affecting the same amino acid (p.Arg188His) was reported in one individual with peritoneum cancer (Table S2, Chan. 2018. PubMed ID: 30093976). In ClinVar, this variant is interpreted as likely benign/uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/246466/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided

Uncertain:1

Nov 17, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

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

Uncertain:1

May 07, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Feb 03, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BMPR1A c.562C>T (p.Arg188Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.4e-05 in 1613616 control chromosomes. The observed variant frequency is approximately 3.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in BMPR1A causing Gastric Cancer phenotype (4e-06). To our knowledge, no occurrence of c.562C>T in individuals affected with Gastric Cancer and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 246466). Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.027

BayesDel_noAF

Benign

-0.26

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.76

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.035

FATHMM_MKL

Uncertain

0.90

M_CAP

Benign

0.018

MetaRNN

Benign

0.26

MetaSVM

Benign

-0.46

MutationAssessor

Benign

1.6

PrimateAI

Benign

0.32

PROVEAN

Benign

-2.2

REVEL

Benign

0.21

Sift

Benign

0.12

Sift4G

Benign

0.089

Polyphen

0.0020

Vest4

0.23

MVP

0.79

MPC

0.53

ClinPred

0.54

GERP RS

3.3

Varity_R

0.088

gMVP

0.48

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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