rs35619497
Positions:
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 4P and 10B. PM5PP2PP3BP4BP6BS1BS2
The NM_004329.3(BMPR1A):c.1327C>T(p.Arg443Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000782 in 1,614,086 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R443H) has been classified as Pathogenic.
Frequency
Genomes: 𝑓 0.00082 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00078 ( 1 hom. )
Consequence
BMPR1A
NM_004329.3 missense
NM_004329.3 missense
Scores
14
2
2
Clinical Significance
Conservation
PhyloP100: 4.08
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -6 ACMG points.
PM5
Other missense variant is known to change same aminoacid residue: Variant chr10-86921681-G-A is described in Lovd as [Pathogenic].
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
Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Dann, Eigen, PrimateAI, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
BP4
Computational evidence support a benign effect (MetaRNN=0.33751726).
BP6
Variant 10-86921680-C-T is Benign according to our data. Variant chr10-86921680-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 133717.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=8, not_provided=1, Benign=5, Uncertain_significance=3}. Variant chr10-86921680-C-T is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000821 (125/152238) while in subpopulation AMR AF= 0.00334 (51/15288). AF 95% confidence interval is 0.00261. There are 0 homozygotes in gnomad4. There are 67 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 125 AD gene.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BMPR1A | NM_004329.3 | c.1327C>T | p.Arg443Cys | missense_variant | 11/13 | ENST00000372037.8 | NP_004320.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BMPR1A | ENST00000372037.8 | c.1327C>T | p.Arg443Cys | missense_variant | 11/13 | 1 | NM_004329.3 | ENSP00000361107 | P1 |
Frequencies
GnomAD3 genomes 0.000822 AC: 125AN: 152120Hom.: 0 Cov.: 32
GnomAD3 genomes
AF:
AC:
125
AN:
152120
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.000676 AC: 170AN: 251490Hom.: 1 AF XY: 0.000611 AC XY: 83AN XY: 135918
GnomAD3 exomes
AF:
AC:
170
AN:
251490
Hom.:
AF XY:
AC XY:
83
AN XY:
135918
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.000778 AC: 1138AN: 1461848Hom.: 1 Cov.: 31 AF XY: 0.000730 AC XY: 531AN XY: 727228
GnomAD4 exome
AF:
AC:
1138
AN:
1461848
Hom.:
Cov.:
31
AF XY:
AC XY:
531
AN XY:
727228
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome 0.000821 AC: 125AN: 152238Hom.: 0 Cov.: 32 AF XY: 0.000900 AC XY: 67AN XY: 74424
GnomAD4 genome
AF:
AC:
125
AN:
152238
Hom.:
Cov.:
32
AF XY:
AC XY:
67
AN XY:
74424
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
TwinsUK
AF:
AC:
0
ALSPAC
AF:
AC:
1
ESP6500AA
AF:
AC:
1
ESP6500EA
AF:
AC:
6
ExAC
AF:
AC:
74
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:15Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:4
| Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Feb 06, 2023 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2022 | BMPR1A: PP3, BS1 - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 27, 2016 | Variant summary: The c.1327C>T in BMPR1A gene is a missense change that involves the alteration of a highly conserved nucleotide and 5/5 in silico tools predict deleterious outcome. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.061%, predominantly in individuals of European and Latino origins (0.08% and 0.13%, respectively). These frequencies exceed the maximal expected allele frequency for a pathogenic variant in BMPR1A (0.0002%). The variant of interest has been reported via reputable database/clinical laboratories as VUS/Benign without evidence to independently evaluate. On the other hand, the variant was identified in JP pt, who reportedly carried a known germline pathogenic mutation in SMAD4 and functional studies showed that R443C expression and BMP signaling levels comparable to wild-type, but it was mislocalized in transfected cells. One other publication reports the variant to co-occur in a patient with a potential pathogenic MSH2 mutation, and an internal sample has a co-occurrence with a pathogenic PMS2 variant, c.2186_2187delTC (classified as pathogenic by LCA). Taken together, this variant has been classified as a Likely Benign. - |
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 26, 2021 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31968564, 28135145, 23399955, 25980754, 15235019, 12417513, 18823382, 28944238, 28873162, 27146957, 28660566, 25637381, 24728327, 24055113, 26976419, 23433720, 25058500, 21153778, 32522605) - |
Generalized juvenile polyposis/juvenile polyposis coli Uncertain:1Benign:3
| Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Nov 21, 2018 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
| Benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Counsyl | Dec 22, 2017 | - - |
| Uncertain significance, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Aug 15, 2016 | Originally interpreted based on literature review PMID: 25637381. Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 60 year old with over 20 adenomatous colon polyps and family history of colon cancer. - |
not specified Uncertain:1Benign:1Other:1
| not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Aug 16, 2021 | - - |
Hereditary cancer-predisposing syndrome Benign:3
| Benign, criteria provided, single submitter | curation | Sema4, Sema4 | Mar 20, 2020 | - - |
| Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 09, 2014 | 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. - |
| Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 09, 2016 | - - |
Juvenile polyposis syndrome Benign:2
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 03, 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 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 17, 2018 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as in patients with juvenile polyps as well as healthy controls [PMID 12417513, 25637381, 24728327, 24055113, 25058500, 23433720, 27146957, 23399955] - |
Carcinoma of colon Benign:1
| Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BMPR1A p.Arg443Cys variant was identified in 7 of 3226 proband chromosomes (frequency: 0.002) from individuals or families with juvenile polyposis, colorectal cancer and Lynch Syndrome, and was present in 1 of 1362 control chromosomes (frequency: 0.007) from healthy individuals (Sayed 2002, Jelsig 2016, Howe 2004, Calva-Cerqueira 2009, Esteban-Jurado 2014, Yurgelun 2015). The variant was identified in dbSNP (rs35619497) as “with other allele”, ClinVar (interpreted as "likely benign" by GeneDx and 4 others, "uncertain significance" by Genetic Services Laboratory and 3 others and "benign" by Invitae and 1 other) and LOVD 3.0 (observed 8x). The variant was identified in control databases in 175 of 277,254 chromosomes (1 homozygous) at a frequency of 0.0006 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 4 of 24,036 chromosomes (freq: 0.0002), Other in 7 of 6468 chromosomes (freq: 0.001), Latino in 58 of 34,420 chromosomes (freq: 0.002), European in 104 of 126,734 chromosomes (freq: 0.0008), Finnish in 2 of 25,794 chromosomes (freq: 0.00008), while the variant was not observed in the Ashkenazi Jewish, East Asian, and South Asian populations. The variant was identified in an individual with a pathogenic MSH2 variant (c.1760-3G>C) (Yurgelun 2015). In HEK-293T cells transfected with the variant, BMPR1A protein was mislocalized, however protein expression and signaling were similar to wild type cells (Howe 2013). The p.Arg443 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. - |
BMPR1A-related disorder Benign:1
| Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 25, 2020 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Uncertain
D
MetaRNN
Benign
T
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at