rs536522394
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
Consequence
NM_000250.2 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000808 AC: 123AN: 152220Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000791 AC: 199AN: 251474Hom.: 0 AF XY: 0.000765 AC XY: 104AN XY: 135914
GnomAD4 exome AF: 0.00114 AC: 1662AN: 1461894Hom.: 1 AF XY: 0.00111 AC XY: 808AN XY: 727248
GnomAD4 genome AF: 0.000807 AC: 123AN: 152338Hom.: 0 Cov.: 32 AF XY: 0.000805 AC XY: 60AN XY: 74492
ClinVar
Submissions by phenotype
not provided Pathogenic:3
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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
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MPO-related disorder Pathogenic:1
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
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at