rs119468010
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 11P and 1B. PM1PP3PP5_Very_StrongBP4
The NM_000250.2(MPO):c.1705C>T(p.Arg569Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00266 in 1,614,180 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 Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.0017 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0028 ( 5 hom. )
Consequence
MPO
NM_000250.2 missense
NM_000250.2 missense
Scores
8
8
3
Clinical Significance
Conservation
PhyloP100: 4.28
Genes affected
MPO (HGNC:7218): (myeloperoxidase) Myeloperoxidase (MPO) is a heme protein synthesized during myeloid differentiation that constitutes the major component of neutrophil azurophilic granules. Produced as a single chain precursor, myeloperoxidase is subsequently cleaved into a light and heavy chain. The mature myeloperoxidase is a tetramer composed of 2 light chains and 2 heavy chains. This enzyme produces hypohalous acids central to the microbicidal activity of neutrophils. [provided by RefSeq, Nov 2014]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PM1
?
In a helix (size 3) in uniprot entity PERM_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000250.2
PP3
?
Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, PROVEAN, REVEL [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
PP5
?
Variant 17-58272835-G-A is Pathogenic according to our data. Variant chr17-58272835-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3626.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-58272835-G-A is described in Lovd as [Pathogenic]. Variant chr17-58272835-G-A is described in Lovd as [Likely_pathogenic]. Variant chr17-58272835-G-A is described in Lovd as [Pathogenic].
BP4
?
Computational evidence support a benign effect (MetaRNN=0.112965494). . Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MPO | NM_000250.2 | c.1705C>T | p.Arg569Trp | missense_variant | 10/12 | ENST00000225275.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MPO | ENST00000225275.4 | c.1705C>T | p.Arg569Trp | missense_variant | 10/12 | 1 | NM_000250.2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00168 AC: 255AN: 152196Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00145 AC: 365AN: 251472Hom.: 0 AF XY: 0.00140 AC XY: 190AN XY: 135920
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GnomAD4 exome AF: 0.00276 AC: 4031AN: 1461866Hom.: 5 Cov.: 31 AF XY: 0.00262 AC XY: 1903AN XY: 727232
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GnomAD4 genome ? AF: 0.00167 AC: 255AN: 152314Hom.: 0 Cov.: 32 AF XY: 0.00138 AC XY: 103AN XY: 74486
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:14Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:8
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 20, 2022 | Published functional studies demonstrate a damaging effect: apopro-MPO does not undergo post-translational processing to enzymatically active MPO resulting in absent MPO activity (Nauseef 1996, Haskamp 2020); 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: 9354683, 9468285, 34662886, 7904599, 15108282, 8142659, 17384005, 24385801, 32758448, 34426522, 31589614, 32531373, 32758447, 8621627) - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Mar 08, 2022 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | May 20, 2021 | PM3_very strong, PS3, PS4_moderate, PP3 - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2021 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The MPO p.R569W variant was identified in the literature in five families with by hereditary myeloperoxidase deficiency in the heterozygous, homozygous and presumed compound heterozygous state. All individuals with p.R569W exhibited abnormal MPO activity, with one homozygous individual being completely MPO deficient while heterozygotes were partially to completely MPO deficient (Nauseef_1998_PMID:9468285). Furthermore, in a cohort of 6 patients with MPO deficiency, one patient was identified to be a compound heterozygote for p.R569W and p.M251T but also had an additional variant in JAK2 (Alexandre_2016_PMID_27013444). The p.R569W variant was identified in dbSNP (ID: rs119468010) and ClinVar (classified as pathogenic by GeneDx). The variant was identified in control databases in 416 of 282876 chromosomes at a frequency of 0.001471 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 370 of 129182 chromosomes (freq: 0.002864), Other in 7 of 7226 chromosomes (freq: 0.000969), European (Finnish) in 13 of 25122 chromosomes (freq: 0.000518), Latino in 14 of 35440 chromosomes (freq: 0.000395), African in 8 of 24968 chromosomes (freq: 0.00032) and South Asian in 4 of 30616 chromosomes (freq: 0.000131), but was not observed in the Ashkenazi Jewish or East Asian populations. The p.R569 residue is conserved in mammals but not in more distantly related 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. Functional studies indicate protein function is affected as a result of this variant, as p.R569W cell lines had a defective maturation process, exhibited no MPO activity compared to wild type cells, failed to incorporate heme, exit the ER, or undergo proteolytic processing to mature MPO subunits and had prolonged association with calnexin and calreticulin compared to complexes with wild type MPO (Sawayama_2008_PMID:18273043; Nauseef_1996_PMID:8621627; Nauseef_1997_PMID:9507022). 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 pathogenic role for this variant. This variant is classified as likely pathogenic. - |
Myeloperoxidase deficiency Pathogenic:4Other:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 26, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Diagnostics Department, Viafet Genomics Laboratory | Aug 23, 2021 | As part of Carrier Screening testing performed at Viafet Genomics Laboratory, this variant was identified in a heterozygous state in a patient who is not affected with this condition. This variant has been identified in a homozygous and compound heterozygous state in patients affected with Myeloperoxidase Deficiency (PMIDs: 7904599, 8142659 and 9468285). - |
not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2004 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Undiagnosed Diseases Network, NIH | May 22, 2023 | - - |
Myeloperoxidase deficiency;C1863052:Alzheimer disease type 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 11, 2022 | - - |
MPO-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | May 01, 2023 | The MPO c.1705C>T variant is predicted to result in the amino acid substitution p.Arg569Trp. This variant has been reported in the homozygous and compound heterozygous state in multiple individuals with myeloperoxidase deficiency (Nauseef et al. 1994. PubMed ID: 7904599; Marchetti et al. 2004. PubMed ID: 15108282; Vergnano et al. 2020. PubMed ID: 32758448). This variant is reported in 0.29% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-56350196-G-A). This variant is interpreted as likely pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;.
MutationTaster
Benign
A;A
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.
REVEL
Pathogenic
Sift
Uncertain
D;.
Sift4G
Uncertain
D;.
Polyphen
D;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at