rs56378716

Positions:

chr17-58279141-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

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

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 made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

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

BS2

High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MPO	NM_000250.2 linkuse as main transcript	c.752T>C	p.Met251Thr	missense_variant	6/12	ENST00000225275.4	NP_000241.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MPO	ENST00000225275.4 linkuse as main transcript	c.752T>C	p.Met251Thr	missense_variant	6/12	1	NM_000250.2	ENSP00000225275	P1	P05164-1
MPO	ENST00000578493.2 linkuse as main transcript	n.27T>C		non_coding_transcript_exon_variant	1/7	3
MPO	ENST00000581022.1 linkuse as main transcript	n.177T>C		non_coding_transcript_exon_variant	2/2	2
MPO	ENST00000699291.1 linkuse as main transcript	c.38T>C	p.Met13Thr	missense_variant, NMD_transcript_variant	1/6			ENSP00000514272

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

GnomAD3 exomes

AF:

0.0102

AC:

2529

AN:

247036

Hom.:

AF XY:

0.00999

AC XY:

1338

AN XY:

133968

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 SAS exome

AF:

0.00162

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

Gnomad4 AFR exome

AF:

0.00185

Gnomad4 AMR exome

AF:

0.00337

Gnomad4 ASJ exome

AF:

0.00954

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00162

Gnomad4 FIN exome

AF:

0.0339

Gnomad4 NFE exome

AF:

0.0126

Gnomad4 OTH exome

AF:

0.00926

GnomAD4 genome

AF:

0.00949

AC:

1445

AN:

152330

Hom.:

Cov.:

AF XY:

0.0102

AC XY:

760

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.00214

Gnomad4 AMR

AF:

0.00529

Gnomad4 ASJ

AF:

0.00778

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.0343

Gnomad4 NFE

AF:

0.0126

Gnomad4 OTH

AF:

0.00851

Alfa

AF:

0.0120

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

Uncertain significance, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2004	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	MPO: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

MPO-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 28, 2024

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

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

MutationTaster

Benign

1.0

A;A

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

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

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