rs536522394
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000250.2(MPO):c.1555_1568delATGGAACCCAACCC(p.Met519ProfsTer21) variant causes a frameshift change. The variant allele was found at a frequency of 0.00111 in 1,614,232 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.00081 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0011 ( 1 hom. )
Consequence
MPO
NM_000250.2 frameshift
NM_000250.2 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.96
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 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-58273466-GGGGTTGGGTTCCAT-G is Pathogenic according to our data. Variant chr17-58273466-GGGGTTGGGTTCCAT-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3629.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-58273466-GGGGTTGGGTTCCAT-G is described in Lovd as [Pathogenic]. Variant chr17-58273466-GGGGTTGGGTTCCAT-G is described in Lovd as [Likely_pathogenic]. Variant chr17-58273466-GGGGTTGGGTTCCAT-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.000808 AC: 123AN: 152220Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000791 AC: 199AN: 251474Hom.: 0 AF XY: 0.000765 AC XY: 104AN XY: 135914
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GnomAD4 exome AF: 0.00114 AC: 1662AN: 1461894Hom.: 1 AF XY: 0.00111 AC XY: 808AN XY: 727248
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GnomAD4 genome 0.000807 AC: 123AN: 152338Hom.: 0 Cov.: 32 AF XY: 0.000805 AC XY: 60AN XY: 74492
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
| Likely pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Mar 17, 2022 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 31, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 19, 2024 | Reported in the compound heterozygous state in a patient with MPO deficiency in published literature (PMID: 9354683); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Published functional studies demonstrate a damaging effect as neutrophils completely deficient in MPO fail to form neutrophil extracellular traps (NETs) (PMID: 20974672); This variant is associated with the following publications: (PMID: 12773517, 32758448, 34426522, 31589614, 33727708, 31980526, 37954595, 32758447, 33531667, 35761024, 20974672, 9354683) - |
Myeloperoxidase deficiency Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 08, 2024 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2004 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 11, 2023 | - - |
MPO-related disorder Pathogenic:1
| Likely pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 19, 2024 | The MPO c.1555_1568del14 variant is predicted to result in a frameshift and premature protein termination (p.Met519Profs*21). This variant was reported as pathogenic for myeloperoxidase deficiency (Romano et al. 1997. PubMed ID: 9354683; Hou et al. 2020. PubMed ID: 31980526; Vergano et al. 2020. PubMed ID: 32758448). This variant is reported in 0.15% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in MPO are expected to be pathogenic. This variant is interpreted as likely pathogenic. - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at