rs56378716

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_000250.2(MPO):c.752T>C(p.Met251Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0115 in 1,612,960 control chromosomes in the GnomAD database, including 147 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0095 ( 14 hom., cov: 32)

Exomes 𝑓: 0.012 ( 133 hom. )

Consequence

MPO
NM_000250.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2B:4

Conservation

PhyloP100: 7.50

Publications

36 publications found

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010124564).

BP6

Variant 17-58279141-A-G is Benign according to our data. Variant chr17-58279141-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3628.

BS2

High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MPO	NM_000250.2 link	c.752T>C	p.Met251Thr	missense_variant	Exon 6 of 12	ENST00000225275.4	NP_000241.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
MPO	ENST00000225275.4 link	c.752T>C	p.Met251Thr	missense_variant	Exon 6 of 12	1	NM_000250.2	ENSP00000225275.3
MPO	ENST00000578493.2 link	n.27T>C		non_coding_transcript_exon_variant	Exon 1 of 7	3
MPO	ENST00000581022.1 link	n.177T>C		non_coding_transcript_exon_variant	Exon 2 of 2	2
MPO	ENST00000699291.1 link	n.38T>C		non_coding_transcript_exon_variant	Exon 1 of 6			ENSP00000514272.1

Frequencies

GnomAD3 genomes

AF:

0.00949

AC:

1444

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00215

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.00530

Gnomad ASJ

AF:

0.00778

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.0343

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0126

Gnomad OTH

AF:

0.00860

GnomAD2 exomes

AF:

0.0102

AC:

2529

AN:

247036

AF XY:

0.00999

show subpopulations

Gnomad AFR exome

AF:

0.00172

Gnomad AMR exome

AF:

0.00336

Gnomad ASJ exome

AF:

0.0104

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0318

Gnomad NFE exome

AF:

0.0135

Gnomad OTH exome

AF:

0.00960

GnomAD4 exome

AF:

0.0117

AC:

17036

AN:

1460630

Hom.:

133

Cov.:

AF XY:

0.0112

AC XY:

8105

AN XY:

726494

show subpopulations

African (AFR)

AF:

0.00185

AC:

AN:

33470

American (AMR)

AF:

0.00337

AC:

150

AN:

44556

Ashkenazi Jewish (ASJ)

AF:

0.00954

AC:

249

AN:

26090

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39662

South Asian (SAS)

AF:

0.00162

AC:

139

AN:

85960

European-Finnish (FIN)

AF:

0.0339

AC:

1808

AN:

53270

Middle Eastern (MID)

AF:

0.00434

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0126

AC:

14043

AN:

1111512

Other (OTH)

AF:

0.00926

AC:

559

AN:

60344

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

1193

2386

3580

4773

5966

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

520

1040

1560

2080

2600

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00949

AC:

1445

AN:

152330

Hom.:

Cov.:

AF XY:

0.0102

AC XY:

760

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.00214

AC:

AN:

41570

American (AMR)

AF:

0.00529

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00778

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00104

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0343

AC:

364

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0126

AC:

858

AN:

68016

Other (OTH)

AF:

0.00851

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

140

210

280

350

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0114

Hom.:

Bravo

AF:

0.00723

TwinsUK

AF:

0.0113

AC:

ALSPAC

AF:

0.0138

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.0135

AC:

116

ExAC

AF:

0.0101

AC:

1229

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Myeloperoxidase deficiency

Pathogenic:1Uncertain:2

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:curation

NM_000250.1:c.752T>C in the MPO gene has an allele frequency of 0.032 in European (Finnish) subpopulation in the gnomAD database. Although a number of 26 homozygous occurrences is observed in the gnomAD database, the majority patients with myeloperoxidase deficiency are asymptomatic clinically except if they are also diabetic. Therefore we determined not to adapt this as a strong benign evidence. Marchetti et al. identified an individual with myeloperoxidase deficiency, harboring a compound heterozygote for c.752T>C and c.1705C>T (PMID: 15108282); and another patient harboring c.752T>C and a 14-base deletion (PMID: 9354683). Conservatively, we interpret it as a variant of uncertain significance in favor of likely pathogenic. ACMG/AMP criteria applied: PM3_Strong, PP4, BS1. -

May 28, 2019

Mendelics

Significance:Uncertain significance

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

- -

not provided

Benign:3

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MPO: BS1, BS2 -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

MPO-related disorder

Benign:1

Jan 28, 2024

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.46

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Uncertain

-0.040

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.71

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.44

MetaRNN

Benign

0.010

MetaSVM

Uncertain

-0.19

MutationAssessor

Uncertain

2.4

PhyloP100

7.5

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-3.1

REVEL

Uncertain

0.57

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0040

Polyphen

0.032

Vest4

0.90

MPC

0.43

ClinPred

0.088

GERP RS

5.5

Varity_R

0.82

gMVP

0.82

Mutation Taster

=39/61

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over