rs28730837

Positions:

chr17-58278036-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_000250.2(MPO):c.995C>T(p.Ala332Val) variant causes a missense change. The variant allele was found at a frequency of 0.0143 in 1,613,622 control chromosomes in the GnomAD database, including 253 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 0.011 ( 31 hom., cov: 32)

Exomes 𝑓: 0.015 ( 222 hom. )

Consequence

MPO
NM_000250.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2B:2

Conservation

PhyloP100: 4.13

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 -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0129981935).

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0146 (21327/1461264) while in subpopulation NFE AF= 0.0165 (18356/1111998). AF 95% confidence interval is 0.0163. There are 222 homozygotes in gnomad4_exome. There are 10245 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 31 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MPO	NM_000250.2 linkuse as main transcript	c.995C>T	p.Ala332Val	missense_variant	7/12	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.995C>T	p.Ala332Val	missense_variant	7/12	1	NM_000250.2	ENSP00000225275	P1	P05164-1
MPO	ENST00000578493.2 linkuse as main transcript	n.270C>T		non_coding_transcript_exon_variant	2/7	3
MPO	ENST00000699291.1 linkuse as main transcript	c.281C>T	p.Ala94Val	missense_variant, NMD_transcript_variant	2/6			ENSP00000514272

Frequencies

GnomAD3 genomes

AF:

0.0112

AC:

1703

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00210

Gnomad AMI

AF:

0.00220

Gnomad AMR

AF:

0.00281

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0491

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0152

Gnomad OTH

AF:

0.00382

GnomAD3 exomes

AF:

0.0124

AC:

3112

AN:

250932

Hom.:

AF XY:

0.0122

AC XY:

1657

AN XY:

135680

show subpopulations

Gnomad AFR exome

AF:

0.00246

Gnomad AMR exome

AF:

0.00150

Gnomad ASJ exome

AF:

0.00159

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0422

Gnomad NFE exome

AF:

0.0181

Gnomad OTH exome

AF:

0.00815

GnomAD4 exome

AF:

0.0146

AC:

21327

AN:

1461264

Hom.:

222

Cov.:

AF XY:

0.0141

AC XY:

10245

AN XY:

726956

show subpopulations

Gnomad4 AFR exome

AF:

0.00248

Gnomad4 AMR exome

AF:

0.00174

Gnomad4 ASJ exome

AF:

0.00172

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0409

Gnomad4 NFE exome

AF:

0.0165

Gnomad4 OTH exome

AF:

0.00992

GnomAD4 genome

AF:

0.0112

AC:

1703

AN:

152358

Hom.:

Cov.:

AF XY:

0.0121

AC XY:

901

AN XY:

74512

show subpopulations

Gnomad4 AFR

AF:

0.00209

Gnomad4 AMR

AF:

0.00281

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0491

Gnomad4 NFE

AF:

0.0152

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.0131

Hom.:

Bravo

AF:

0.00818

TwinsUK

AF:

0.0132

AC:

ALSPAC

AF:

0.0174

AC:

ESP6500AA

AF:

0.00295

AC:

ESP6500EA

AF:

0.0135

AC:

116

ExAC

AF:

0.0132

AC:

1609

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0140

EpiControl

AF:

0.0126

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Myeloperoxidase deficiency

Pathogenic:1Uncertain:2Benign:1

Uncertain significance, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_000250.1:c.995C>T in the MPO gene has an allele frequency of 0.043 in European (Finnish) subpopulation in the gnomAD database. Mutations in the MPO gene lead to Hereditary myeloperoxidase (MPO) deficiency in an autosomal recessive manner. Although a number of 45 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 a individual with a partial myeloperoxidase deficiency, harboring the compound heterozygote for this variant and c.1715T>G (PMID: 15108282). Conservatively, we interpret it as variant of uncertain significance (VUS). ACMG/AMP criteria applied: PM3, PP4, BS1. -
Likely benign, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	-	The heterozygous p.Ala332Val variant in MPO has been identified in 2 individuals with myeloperoxidase deficiency (PMID: 15108282), but has also been identified in >4% of European (Finnish) chromosomes and 27 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for autosomal recessive myeloperoxidase deficiency. -
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:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2022

MPO: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.34

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.62

Eigen

Benign

0.17

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.89

MetaRNN

Benign

0.013

MetaSVM

Benign

-0.75

MutationAssessor

Benign

1.6

MutationTaster

Benign

0.98

A;A

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.21

Sift

Benign

0.084

Sift4G

Uncertain

0.059

Polyphen

0.89

Vest4

0.10

MPC

0.41

ClinPred

0.020

GERP RS

4.3

Varity_R

0.64

gMVP

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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