rs536522394

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_000250.2(MPO):c.1555_1568delATGGAACCCAACCC(p.Met519ProfsTer21) variant causes a frameshift change. The variant allele was found at a frequency of 0.00111 in 1,614,232 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00081 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 1 hom. )

Consequence

MPO
NM_000250.2 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 6.96

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: Pathogenic. The variant received 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 17-58273466-GGGGTTGGGTTCCAT-G is Pathogenic according to our data. Variant chr17-58273466-GGGGTTGGGTTCCAT-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3629.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-58273466-GGGGTTGGGTTCCAT-G is described in Lovd as [Pathogenic]. Variant chr17-58273466-GGGGTTGGGTTCCAT-G is described in Lovd as [Likely_pathogenic]. Variant chr17-58273466-GGGGTTGGGTTCCAT-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MPO	NM_000250.2 link	c.1555_1568delATGGAACCCAACCC	p.Met519ProfsTer21	frameshift_variant	Exon 9 of 12	ENST00000225275.4	NP_000241.1	P05164-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MPO	ENST00000225275.4 link	c.1555_1568delATGGAACCCAACCC	p.Met519ProfsTer21	frameshift_variant	Exon 9 of 12	1	NM_000250.2	ENSP00000225275.3		P05164-1

Frequencies

GnomAD3 genomes

AF:

0.000808

AC:

123

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00153

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000791

AC:

199

AN:

251474

AF XY:

0.000765

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000347

Gnomad ASJ exome

AF:

0.00109

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00149

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.00114

AC:

1662

AN:

1461894

Hom.:

AF XY:

0.00111

AC XY:

808

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

AC:

AN:

33480

Gnomad4 AMR exome

AF:

0.000313

AC:

AN:

44724

Gnomad4 ASJ exome

AF:

0.00153

AC:

AN:

26136

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39700

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

86258

Gnomad4 FIN exome

AF:

0.0000562

AC:

AN:

53420

Gnomad4 NFE exome

AF:

0.00140

AC:

1552

AN:

1112012

Gnomad4 Remaining exome

AF:

0.000662

AC:

AN:

60396

Heterozygous variant carriers

106

212

318

424

530

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

112

168

224

280

<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:

0.000807

AC:

123

AN:

152338

Hom.:

Cov.:

AF XY:

0.000805

AC XY:

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.000120

AC:

0.000120279

AN:

0.000120279

Gnomad4 AMR

AF:

0.000523

AC:

0.000522739

AN:

0.000522739

Gnomad4 ASJ

AF:

0.00144

AC:

0.00144009

AN:

0.00144009

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.00153

AC:

0.0015286

AN:

0.0015286

Gnomad4 OTH

AF:

0.000473

AC:

0.000473485

AN:

0.000473485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<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:

0.000344

Hom.:

Bravo

AF:

0.000778

EpiCase

AF:

0.00180

EpiControl

AF:

0.00190

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Myeloperoxidase deficiency

Pathogenic:4

May 01, 2004

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Jan 08, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 11, 2023

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 28, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

not provided

Pathogenic:3

Mar 17, 2022

AiLife Diagnostics, AiLife Diagnostics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 19, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported in the compound heterozygous state in a patient with MPO deficiency in published literature (PMID: 9354683); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Published functional studies demonstrate a damaging effect as neutrophils completely deficient in MPO fail to form neutrophil extracellular traps (NETs) (PMID: 20974672); This variant is associated with the following publications: (PMID: 12773517, 32758448, 34426522, 31589614, 33727708, 31980526, 37954595, 32758447, 33531667, 35761024, 20974672, 9354683) -

Jan 31, 2017

CeGaT Center for Human Genetics Tuebingen

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

MPO-related disorder

Pathogenic:1

Sep 19, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The MPO c.1555_1568del14 variant is predicted to result in a frameshift and premature protein termination (p.Met519Profs*21). This variant was reported as pathogenic for myeloperoxidase deficiency (Romano et al. 1997. PubMed ID: 9354683; Hou et al. 2020. PubMed ID: 31980526; Vergano et al. 2020. PubMed ID: 32758448). This variant is reported in 0.15% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in MPO are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Mutation Taster

=2/198

disease causing (ClinVar)

Splicing

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