chr10-86921596-G-A
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 4P and 13B. PM5PP2PP3BP4_StrongBP6BS1BS2
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
Consequence
NM_004329.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
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: 83AN: 152154Hom.: 2 Cov.: 32
GnomAD3 exomes AF: 0.000887 AC: 223AN: 251480Hom.: 1 AF XY: 0.000898 AC XY: 122AN XY: 135918
GnomAD4 exome AF: 0.000487 AC: 712AN: 1461870Hom.: 3 Cov.: 31 AF XY: 0.000506 AC XY: 368AN XY: 727238
GnomAD4 genome AF: 0.000545 AC: 83AN: 152272Hom.: 2 Cov.: 32 AF XY: 0.000551 AC XY: 41AN XY: 74454
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign: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 | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2024 | BMPR1A: PP3, BS1 - |
Likely benign, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jan 24, 2018 | - - |
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) - |
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, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 14, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 27, 2017 | - - |
not specified Uncertain:1Benign:2Other:1
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jan 13, 2020 | - - |
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. - |
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 | - - |
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 | - - |
Benign, criteria provided, single submitter | curation | Sema4, Sema4 | Jul 28, 2020 | - - |
Generalized juvenile polyposis/juvenile polyposis coli Benign:3
Benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
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. - |
Juvenile polyposis syndrome Benign:2
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. - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at