rs536522394

Positions:

• chr17-58273466-GGGGTTGGGTTCCAT-G
• chr17-58273466-GGGGTTGGGTTCCAT-GGGGTTGGGTTCCATGGGTTGGGTTCCAT

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 6.96

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 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	Protein	UniProt
MPO	NM_000250.2	c.1555_1568del	p.Met519ProfsTer21	frameshift_variant	9/12	ENST00000225275.4	NP_000241.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MPO	ENST00000225275.4	c.1555_1568del	p.Met519ProfsTer21	frameshift_variant	9/12	1	NM_000250.2	ENSP00000225275	P1

Frequencies

GnomAD3 genomes AF: 0.000808 AC: 123 AN: 152220 Hom.: 0 Cov.: 32

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.: 0 AF XY: 0.000765 AC XY: 104 AN XY: 135914

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.: 1 AF XY: 0.00111 AC XY: 808 AN XY: 727248

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.: 0 Cov.: 32 AF XY: 0.000805 AC XY: 60 AN XY: 74492

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.: 0

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

Submissions by phenotype

not provided Pathogenic:3

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. -
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	- -

Myeloperoxidase deficiency Pathogenic:3

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

MPO-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 19, 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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs536522394; hg19: chr17-56350827;