rs35897051
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1PP3_StrongPP5
The NM_000250.2(MPO):c.2031-2A>C variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00554 in 1,612,874 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000250.2 splice_acceptor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MPO | NM_000250.2 | c.2031-2A>C | splice_acceptor_variant | ENST00000225275.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MPO | ENST00000225275.4 | c.2031-2A>C | splice_acceptor_variant | 1 | NM_000250.2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00456 AC: 693AN: 152044Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00437 AC: 1098AN: 251174Hom.: 2 AF XY: 0.00411 AC XY: 558AN XY: 135856
GnomAD4 exome AF: 0.00565 AC: 8250AN: 1460712Hom.: 25 Cov.: 31 AF XY: 0.00550 AC XY: 3999AN XY: 726678
GnomAD4 genome ? AF: 0.00455 AC: 693AN: 152162Hom.: 0 Cov.: 32 AF XY: 0.00413 AC XY: 307AN XY: 74386
ClinVar
Submissions by phenotype
Myeloperoxidase deficiency Pathogenic:10Other:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 01, 2019 | This variant was identified as compound heterozygous. - |
Pathogenic, no assertion criteria provided | curation | Reproductive Health Research and Development, BGI Genomics | Jan 06, 2020 | NG_009629.1(NM_000250.1):c.2031-2A>C in the MPO gene has an allele frequency of 0.013 in Ashkenazi Jewish subpopulation in the gnomAD database. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. It was detected in individual with autosomal recessive Myeloperoxidase deficiency, compound heterozygous with c.1566_1579del14 (PMID:15108282). The patient's phenotype is highly specific for the MPO gene (PMID:15108282). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP criteria applied:PVS1; PM3; PP4; BS1. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2004 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 26, 2014 | The 2031-2A>C variant in MPO has been previously identified in 1 compound heterozygous and 2 homozygous individuals with myeloperoxidase deficiency (Marchetti 2004). This variant is located in the 3' splice region and functional studies indicate that this variant leads to altered splicing (Marchetti 2004). In summary, the 2031-2A>C variant meets our criteria to be considered causative for myeloperoxidase deficiency (MPOD) in a recessive manner. However, the clinical relevance of MPOD is not well-established. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 02, 2023 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Clinic of Clinical Immunology with Stem Cell Bank, Expert Centre for Rare Diseases - PID, University Hospital "Alexandrovska" | May 01, 2022 | - - |
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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Jul 08, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Payam Genetics Center, General Welfare Department of North Khorasan Province | Mar 01, 2023 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Undiagnosed Diseases Network, NIH | May 22, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 26, 2024 | - - |
not provided Pathogenic:7
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 27, 2022 | Reported as a heterozygous germline variant in multiple individuals with myeloid neoplasms (Kongkiatkamon et al., 2022); Splice site variant that destroys the canonical splice acceptor site in intron 11, and causes the activation of a cryptic splice site located 109 nucleotides upstream of the authentic splice site (Marchetti et al., 2004); This variant is associated with the following publications: (PMID: 20974672, 25714468, 34662886, 35026467, 24385801, 17384005, 15108282, 26764160, 26822949, 27301573, 27827828, 30487145, 31980526, 32758448, 34426522, 32758447, 32531373, 35761024) - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2024 | MPO: PM3, PS3:Moderate, PM2:Supporting, PP3 - |
Likely pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Mar 30, 2022 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Myeloperoxidase deficiency;C1863052:Alzheimer disease type 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 12, 2022 | - - |
MPO-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 26, 2024 | The MPO c.2031-2A>C variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported to be causative for autosomal recessive myeloperoxidase deficiency (Marchetti et al. 2004. PubMed ID: 15108282; Vergnano et al. 2020. PubMed ID: 32758448). This variant is reported in 1.3% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. Variants that disrupt the consensus splice acceptor site in MPO are expected to be pathogenic, and this variant has been classified as pathogenic or likely pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/3632). This variant is interpreted as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at