rs536522394

Variant names:

• chr17-58273466-GGGGTTGGGTTCCAT-G
• rs536522394
• NM_000250.2:c.1555_1568delATGGAACCCAACCC

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_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. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. 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:9
• Conservation: PhyloP100: 6.96
• Publications: 8 publications found

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

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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 3629.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000250.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MPO	NM_000250.2	MANE Select	c.1555_1568delATGGAACCCAACCC	p.Met519ProfsTer21	frameshift	Exon 9 of 12	NP_000241.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MPO	ENST00000225275.4	TSL:1 MANE Select	c.1555_1568delATGGAACCCAACCC	p.Met519ProfsTer21	frameshift	Exon 9 of 12	ENSP00000225275.3
	MPO	ENST00000577220.1	TSL:3	c.13_26delATGGAACCCAACCC	p.Met5ProfsTer21	frameshift	Exon 1 of 3	ENSP00000464668.1
	MPO	ENST00000578493.2	TSL:3	n.888_901delATGGAACCCAACCC		non_coding_transcript_exon	Exon 4 of 7

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

GnomAD2 exomes AF: 0.000791 AC: 199 AN: 251474 AF XY: 0.000765

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

African (AFR) AF: 0.000269 AC: 9 AN: 33480

American (AMR) AF: 0.000313 AC: 14 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00153 AC: 40 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53420

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.00140 AC: 1552 AN: 1112012

Other (OTH) AF: 0.000662 AC: 40 AN: 60396

GnomAD4 genome AF: 0.000807 AC: 123 AN: 152338 Hom.: 0 Cov.: 32 AF XY: 0.000805 AC XY: 60 AN XY: 74492

African (AFR) AF: 0.000120 AC: 5 AN: 41570

American (AMR) AF: 0.000523 AC: 8 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00153 AC: 104 AN: 68036

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000344 Hom.: 0

Bravo AF: 0.000778

EpiCase AF: 0.00180

EpiControl AF: 0.00190

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Myeloperoxidase deficiency (4)
4	-	-	not provided (4)
1	-	-	MPO-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.0
Mutation Taster		=2/198	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs536522394; hg19: chr17-56350827;