Variant chr17-58273466-GGGGTTGGGTTCCAT-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000250.2(MPO):c.1555_1568del(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:7

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

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

PM2

Very rare variant in population databases, with high coverage;

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/exons	MANE	UniProt
MPO	NM_000250.2 linkuse as main transcript	c.1555_1568del	p.Met519ProfsTer21	frameshift_variant	9/12	ENST00000225275.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MPO	ENST00000225275.4 linkuse as main transcript	c.1555_1568del	p.Met519ProfsTer21	frameshift_variant	9/12	1	NM_000250.2	P1	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

GnomAD3 exomes

AF:

0.000791

AC:

199

AN:

251474

Hom.:

AF XY:

0.000765

AC XY:

104

AN XY:

135914

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 SAS 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

Gnomad4 AMR exome

AF:

0.000313

Gnomad4 ASJ exome

AF:

0.00153

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.00140

Gnomad4 OTH exome

AF:

0.000662

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

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00153

Gnomad4 OTH

AF:

0.000473

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:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Mar 17, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 31, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 26, 2016	The c.1555_1568del14 pathogenic variant in the MPO gene has been reported previously in association with myeloperoxidase deficiency, in a father who was compound heterozygous for c.1555_1568del14 and another variant and his daughter who was heterozygous for c.1555_1568del14 and no second variant (Romano et al., 1997). The c.1555_1568del14 variant causes a frameshift starting with codon Methionine 519, changes this amino acid to a Proline residue, and creates a premature Stop codon at position 21 of the new reading frame, denoted p.Met519ProfsX21. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Functional studies show neutrophils from donors who are compound heterozygous for the c.1555_1568del14 variant and another pathogenic variant fail to form neutrophil extracellular traps (Metzler et al., 2011). The c.1555_1568del14 variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.1555_1568del14 as a pathogenic variant. -

Myeloperoxidase deficiency

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 11, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2004	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 08, 2024	- -

MPO-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 05, 2024

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

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