rs35897051

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1PP5

The NM_000250.2(MPO):​c.2031-2A>C variant causes a splice acceptor, intron 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

Genomes: 𝑓 0.0046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0056 ( 25 hom. )

Consequence

MPO
NM_000250.2 splice_acceptor, intron

Scores

4
2
1
Splicing: ADA: 1.000
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:19U:1O:1

Conservation

PhyloP100: 8.01
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease,
PP5
Variant 17-58270865-T-G is Pathogenic according to our data. Variant chr17-58270865-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 3632.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=6, Likely_pathogenic=5, not_provided=1}. Variant chr17-58270865-T-G is described in Lovd as [Pathogenic]. Variant chr17-58270865-T-G is described in Lovd as [Likely_pathogenic]. Variant chr17-58270865-T-G is described in Lovd as [Likely_pathogenic]. Variant chr17-58270865-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MPONM_000250.2 linkc.2031-2A>C splice_acceptor_variant, intron_variant Intron 11 of 11 ENST00000225275.4 NP_000241.1 P05164-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MPOENST00000225275.4 linkc.2031-2A>C splice_acceptor_variant, intron_variant Intron 11 of 11 1 NM_000250.2 ENSP00000225275.3 P05164-1

Frequencies

GnomAD3 genomes
AF:
0.00456
AC:
693
AN:
152044
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00116
Gnomad AMI
AF:
0.00219
Gnomad AMR
AF:
0.00576
Gnomad ASJ
AF:
0.0150
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00132
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00703
Gnomad OTH
AF:
0.00526
GnomAD3 exomes
AF:
0.00437
AC:
1098
AN:
251174
Hom.:
2
AF XY:
0.00411
AC XY:
558
AN XY:
135856
show subpopulations
Gnomad AFR exome
AF:
0.000862
Gnomad AMR exome
AF:
0.00283
Gnomad ASJ exome
AF:
0.0121
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.0000980
Gnomad FIN exome
AF:
0.00171
Gnomad NFE exome
AF:
0.00715
Gnomad OTH exome
AF:
0.00196
GnomAD4 exome
AF:
0.00565
AC:
8250
AN:
1460712
Hom.:
25
Cov.:
31
AF XY:
0.00550
AC XY:
3999
AN XY:
726678
show subpopulations
Gnomad4 AFR exome
AF:
0.000628
Gnomad4 AMR exome
AF:
0.00266
Gnomad4 ASJ exome
AF:
0.0129
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.000128
Gnomad4 FIN exome
AF:
0.00247
Gnomad4 NFE exome
AF:
0.00659
Gnomad4 OTH exome
AF:
0.00486
GnomAD4 genome
AF:
0.00455
AC:
693
AN:
152162
Hom.:
0
Cov.:
32
AF XY:
0.00413
AC XY:
307
AN XY:
74386
show subpopulations
Gnomad4 AFR
AF:
0.00116
Gnomad4 AMR
AF:
0.00575
Gnomad4 ASJ
AF:
0.0150
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00132
Gnomad4 NFE
AF:
0.00703
Gnomad4 OTH
AF:
0.00521
Alfa
AF:
0.00642
Hom.:
2
Bravo
AF:
0.00400
TwinsUK
AF:
0.00755
AC:
28
ALSPAC
AF:
0.00649
AC:
25
ESP6500AA
AF:
0.00136
AC:
6
ESP6500EA
AF:
0.00721
AC:
62
ExAC
AF:
0.00424
AC:
515
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.00600
EpiControl
AF:
0.00557

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:19Uncertain:1Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Myeloperoxidase deficiency Pathogenic:10Other:1
Jan 06, 2020
Reproductive Health Research and Development, BGI Genomics
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: curation

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. -

Nov 02, 2023
Revvity Omics, Revvity
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 01, 2004
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

May 01, 2022
Clinic of Clinical Immunology with Stem Cell Bank, Expert Centre for Rare Diseases - PID, University Hospital "Alexandrovska"
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Sep 26, 2014
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Jul 08, 2019
Knight Diagnostic Laboratories, Oregon Health and Sciences University
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 01, 2023
Payam Genetics Center, General Welfare Department of North Khorasan Province
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 01, 2019
Institute of Human Genetics, University of Leipzig Medical Center
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was identified as compound heterozygous. -

-
GenomeConnect, ClinGen
Significance: not provided
Review Status: no classification provided
Collection Method: phenotyping only

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. -

Mar 26, 2024
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 22, 2023
Undiagnosed Diseases Network, NIH
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

not provided Pathogenic:7
Mar 30, 2022
AiLife Diagnostics, AiLife Diagnostics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Nov 16, 2024
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Reported as a heterozygous germline variant in multiple individuals with myeloid neoplasms (PMID: 35761024); 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 (PMID: 15108282); This variant is associated with the following publications: (PMID: 20974672, 25714468, 34662886, 35026467, 24385801, 17384005, 15108282, 26764160, 26822949, 27301573, 27827828, 30487145, 31980526, 32758448, 34426522, 32531373, 35761024, 36730508, 37868038, 38170104, 32758447) -

-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jan 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

MPO: PM3, PS3:Moderate, PM2:Supporting, PP3 -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Nov 03, 2021
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Myeloperoxidase deficiency;C1863052:Alzheimer disease type 1 Pathogenic:1
Apr 12, 2022
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

MPO-related disorder Pathogenic:1
Sep 05, 2024
PreventionGenetics, part of Exact Sciences
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

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. -

not specified Uncertain:1
May 01, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: MPO c.2031-2A>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 3' acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing , and the predominant products were truncated MPO (Haskamp_2020), such mRNA products are not subject to NMD. The variant allele was found at a frequency of 0.0044 in 251174 control chromosomes in the gnomAD database, including 2 homozygotes (gnomAD v2), and in gnomAD v4 dataset, this vairant was found a frequency of 0.0066 in 1179978 control chromosomes in European (non-Finnish) group with 25 homozygotes, suggesting that the variant may be benign. c.2031-2A>C has been reported in the literature in at-least three individuals affected with Myeloperoxidase Deficiency (example, Marchetti_2004). Additionally, no pathogenic missense or in-frame changes from the last exon have been reported in ClinVar, suggesting the disrupted last exon may not be functionally important. The following publications have been ascertained in the context of this evaluation (PMID: 32758447, 15108282). ClinVar contains an entry for this variant (Variation ID: 3632). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.28
D
BayesDel_noAF
Pathogenic
0.29
CADD
Pathogenic
29
DANN
Uncertain
1.0
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.94
FATHMM_MKL
Uncertain
0.96
D
GERP RS
5.4

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.94
SpliceAI score (max)
0.98
Details are displayed if max score is > 0.2
DS_AL_spliceai
0.98
Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs35897051; hg19: chr17-56348226; API