chr17-58272835-G-A

Position:

chr17-58272835-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 9P and 1B. PP3PP5_Very_StrongBP4

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

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.28

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]

MPO links:

MPO (HGNC:):

MPO links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

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	Protein	UniProt
MPO	NM_000250.2 linkuse as main transcript	c.1705C>T	p.Arg569Trp	missense_variant	10/12	ENST00000225275.4	NP_000241.1	P05164-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MPO	ENST00000225275.4 linkuse as main transcript	c.1705C>T	p.Arg569Trp	missense_variant	10/12	1	NM_000250.2	ENSP00000225275.3		P05164-1

Frequencies

GnomAD3 genomes

AF:

0.00168

AC:

255

AN:

152196

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00140

AC XY:

190

AN XY:

135920

show subpopulations

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.:

Cov.:

AF XY:

0.00262

AC XY:

1903

AN XY:

727232

show subpopulations

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.:

Cov.:

AF XY:

0.00138

AC XY:

103

AN XY:

74486

show subpopulations

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.:

Bravo

AF:

0.00178

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00493

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00291

AC:

ExAC

AF:

0.00155

AC:

188

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00234

EpiControl

AF:

0.00202

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 04, 2024	Published functional studies demonstrate a damaging effect: apopro-MPO does not undergo post-translational processing to enzymatically active MPO resulting in absent MPO activity (PMID: 8621627, 32758447); 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, 35761024, 8621627) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Mar 08, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
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, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 20, 2021	PM3_very strong, PS3, PS4_moderate, PP3 -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Myeloperoxidase deficiency

Pathogenic:4Other: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	clinical testing	Undiagnosed Diseases Network, NIH	May 22, 2023	- -
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. -

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, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 05, 2024

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. 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

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.85

D;T

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.95

D;D

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.11

T;T

MetaSVM

Uncertain

0.45

MutationAssessor

Uncertain

2.9

M;.

PrimateAI

Uncertain

0.58

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

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over