rs119468010

chr17-58272835-G-Achr17-58272835-G-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 11P and 1B. PM1 PP3 PP5_Very_Strong BP4

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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14 O:1
• 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]

ACMG classification

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: 255 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000719

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00306

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00145 AC: 365 AN: 251472 Hom.: 0 AF XY: 0.00140 AC XY: 190 AN XY: 135920

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.000554

Gnomad NFE exome AF: 0.00286

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.00276 AC: 4031 AN: 1461866 Hom.: 5 Cov.: 31 AF XY: 0.00262 AC XY: 1903 AN XY: 727232

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.000447

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000290

Gnomad4 FIN exome AF: 0.000524

Gnomad4 NFE exome AF: 0.00343

Gnomad4 OTH exome AF: 0.00217

GnomAD4 genome AF: 0.00167 AC: 255 AN: 152314 Hom.: 0 Cov.: 32 AF XY: 0.00138 AC XY: 103 AN XY: 74486

Gnomad4 AFR AF: 0.000698

Gnomad4 AMR AF: 0.000718

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00306

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00264 Hom.: 1

Bravo AF: 0.00178

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00291 AC: 25

ExAC AF: 0.00155 AC: 188

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00234

EpiControl AF: 0.00202

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:8

Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Mar 08, 2022	- -
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	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2021	- -
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	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) -
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. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Myeloperoxidase deficiency Pathogenic:4 Other: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). -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2004	- -
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	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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Benign	-0.0064	T
BayesDel_noAF	Pathogenic	0.22
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.85	D;T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.11	T;T
MetaSVM	Uncertain	0.45	D
MutationAssessor	Uncertain	2.9	M;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-5.6	D;.
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0050	D;.
Polyphen		1.0	D;.
Vest4		0.95
MVP		0.99
MPC		1.0
ClinPred		0.063	T
GERP RS		5.1
Varity_R		0.93
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs119468010; hg19: chr17-56350196; COSMIC: COSV104554515; COSMIC: COSV104554515;