rs35619497

Positions:

• chr10-86921680-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 4P and 10B. PM5 PP2 PP3 BP4 BP6 BS1 BS2

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 Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00082 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00078 (1 hom.)
• Consequence: BMPR1A NM_004329.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:15 O:1
• 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]

ACMG classification

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 ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 231433.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}.
• PP2: Missense variant where missense usually causes diseases, BMPR1A
• 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: {Benign=5, Likely_benign=9, not_provided=1, 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	UniProt
BMPR1A	NM_004329.3	c.1327C>T	p.Arg443Cys	missense_variant	11/13	ENST00000372037.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMPR1A	ENST00000372037.8	c.1327C>T	p.Arg443Cys	missense_variant	11/13	1	NM_004329.3	P1

Frequencies

GnomAD3 genomes AF: 0.000822 AC: 125 AN: 152120 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000823

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000676 AC: 170 AN: 251490 Hom.: 1 AF XY: 0.000611 AC XY: 83 AN XY: 135918

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00176

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000870

Gnomad OTH exome AF: 0.000814

GnomAD4 exome AF: 0.000778 AC: 1138 AN: 1461848 Hom.: 1 Cov.: 31 AF XY: 0.000730 AC XY: 531 AN XY: 727228

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.00217

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000206

Gnomad4 NFE exome AF: 0.000888

Gnomad4 OTH exome AF: 0.000596

GnomAD4 genome AF: 0.000821 AC: 125 AN: 152238 Hom.: 0 Cov.: 32 AF XY: 0.000900 AC XY: 67 AN XY: 74424

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.00334

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.000823

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000920 Hom.: 0

Bravo AF: 0.00120

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000610 AC: 74

EpiCase AF: 0.00109

EpiControl AF: 0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:15 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:4

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 06, 2023	- -
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	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) -
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	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	BMPR1A: PP3, BS1 -

Generalized juvenile polyposis/juvenile polyposis coli Uncertain:1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Dec 22, 2017	- -
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. -
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:1 Benign:1 Other: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

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 09, 2016	- -
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. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Mar 20, 2020	- -

Juvenile polyposis syndrome Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

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, criteria provided, single submitter

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.34	T
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Uncertain	2.8	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.80	D
PROVEAN	Pathogenic	-7.9	D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.88
MVP		0.98
MPC		1.8
ClinPred		0.19	T
GERP RS		5.6
Varity_R		0.89
gMVP		0.92

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: rs35619497; hg19: chr10-88681437; COSMIC: COSV64407977;