rs140592056

chr10-86921596-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 4P and 13B. PM5 PP2 PP3 BP4_Strong BP6 BS1 BS2

The NM_004329.3(BMPR1A):c.1243G>A(p.Glu415Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000493 in 1,614,142 control chromosomes in the GnomAD database, including 5 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. E415D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00055 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00049 (3 hom.)
• Consequence: BMPR1A NM_004329.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:19 O:1
• Conservation: PhyloP100: 9.93

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 Benign. Variant got -9 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-86921596-GA-TTTC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 422244.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, BMPR1A
• PP3: Multiple lines of computational evidence support a deleterious effect 8: BayesDel_addAF, BayesDel_noAF, Cadd, Dann, Eigen, phyloP100way_vertebrate, PrimateAI, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationAssessor, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.03156662).
• BP6: Variant 10-86921596-G-A is Benign according to our data. Variant chr10-86921596-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 41779.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=11, Benign=5, not_provided=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000545 (83/152272) while in subpopulation AMR AF= 0.00072 (11/15286). AF 95% confidence interval is 0.000403. There are 2 homozygotes in gnomad4. There are 41 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 83 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BMPR1A	NM_004329.3	c.1243G>A	p.Glu415Lys	missense_variant	11/13	ENST00000372037.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMPR1A	ENST00000372037.8	c.1243G>A	p.Glu415Lys	missense_variant	11/13	1	NM_004329.3	P1

Frequencies

GnomAD3 genomes AF: 0.000545 AC: 83 AN: 152154 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000721

Gnomad ASJ AF: 0.0159

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000887 AC: 223 AN: 251480 Hom.: 1 AF XY: 0.000898 AC XY: 122 AN XY: 135918

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.0165

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000299

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000487 AC: 712 AN: 1461870 Hom.: 3 Cov.: 31 AF XY: 0.000506 AC XY: 368 AN XY: 727238

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.0160

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000147

Gnomad4 OTH exome AF: 0.00142

GnomAD4 genome AF: 0.000545 AC: 83 AN: 152272 Hom.: 2 Cov.: 32 AF XY: 0.000551 AC XY: 41 AN XY: 74454

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000720

Gnomad4 ASJ AF: 0.0159

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.00235 Hom.: 0

Bravo AF: 0.000661

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000684 AC: 83

EpiCase AF: 0.000600

EpiControl AF: 0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:19 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:7

Uncertain significance, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 30, 2020	This variant is associated with the following publications: (PMID: 27621404, 25722345, 27878467, 24728327, 25637381, 25980754, 22703879, 23399955, 25801821, 27153395, 27884173, 24448499, 30680046) -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 14, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 02, 2016	Variant summary: The BMPR1A c.1243G>A (p.Glu415Lys) variant involves the alteration of a conserved nucleotide. Glu415Lys occurs at a position that is conserved across mammals and is located in the protein kinase domain, and 4/5 in silico tools predict a damaging outcome for this variant. This variant was found in 87/122544 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0011238 (75/66740). This frequency is about 562 times the estimated maximal expected allele frequency of a pathogenic BMPR1A variant (0.000002), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. This variant was also observed in three individuals with a history of moderate-load polyposis; reported pathology included hyperplastic, hamartomatous, juvenile and adenomatous polyps (Ngeow 2013); and in one individual undergoing hereditary panel testing for a personal and/or family history suspicious for Lynch syndrome (Yurgelun 2015). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance or likely benign. Taken together and based on the prevalence in the general population, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	May 03, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 24, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Dec 27, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	BMPR1A: PP3, BS1 -

not specified Uncertain:1 Benign:2 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 31, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant is present in HGMD in 5 papers, with comments suggesting likely benign. The variant is present in ExAC at a Max MAF of 0.11% and at 1.6% (165) of Ashkenazi alleles in gnomAD - frequency too high for disease. It is classified as Likely Benign by 4 submitters (GeneDx, Invitae, Ambry, CSER_CC_NCGL) and as VUS by Biesecker lab. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 13, 2020	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Hereditary cancer-predisposing syndrome Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 19, 2016	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 28, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 31, 2018	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. -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Sep 13, 2017	- -

Generalized juvenile polyposis/juvenile polyposis coli Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Mar 12, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 12, 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	- -

Juvenile polyposis syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 02, 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. -

Malignant tumor of breast Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

BMPR1A, EXON11, c.1243G>A, p.Glu415Lys, Heterozygous, Uncertain SignificancernThe BMPR1A p.Glu415Lys variant was identified in 15 of 11178 proband chromosomes (frequency: 0.001) from individuals or families with breast cancer, Lynch Syndrome, or undefined moderate load gastrointestinal polyposis and was present in 2 of 1362 control chromosomes (frequency: 0.002) from healthy individuals (Balmana 2016, Ngeow 2013, Tung 2015, Yurgelun 2015, Bodian 2014). The variant was also identified in dbSNP (ID: rs140592056) as "With other allele", ClinVar (classified as benign by Invitae and Integrated Genetics/Laboratory Corporation of America; as likely benign by GeneDx, Ambry Genetics, PreventionGenetics, and six other submitters; and as uncertain significance by two submitters), and LOVD 3.0 (1x as VUS). The variant was identified in control databases in 221 of 277220 chromosomes (1 homozygous) at a frequency of 0.0008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 161 of 10152 chromosomes (freq: 0.02, increasing the likelihood this could be a low frequency benign variant), African in 1 of 24028 chromosomes (freq: 0.00004), Other in 7 of 6466 chromosomes (freq: 0.001), Latino in 10 of 34420 chromosomes (freq: 0.0003), European in 39 of 126714 chromosomes (freq: 0.0003), East Asian in 1 of 18870 chromosomes (freq: 0.00005), and South Asian in 2 of 30782 chromosomes (freq: 0.00006); it was not observed in the Finnish population. The p.Glu415 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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. This variant is classified as a variant of uncertain significance.rnAssessment Date: 2019/07/23rnReferences (PMIDs): 27621404, 23399955, 25186627, 25980754, 24728327 -

Gastrointestinal polyposis Benign:1

Likely benign, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.36
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.71	D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.032	T
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.3	D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.92
MVP		0.96
MPC		0.96
ClinPred		0.074	T
GERP RS		5.6
Varity_R		0.77
gMVP		0.74

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: rs140592056; hg19: chr10-88681353; COSMIC: COSV100923714;