rs28730837

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

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

Publications

30 publications found

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 was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

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

BP6

Variant 17-58278036-G-A is Benign according to our data. Variant chr17-58278036-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 3630. Variant chr17-58278036-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 3630.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 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 GnomAdExome4. There are 10245 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 31 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MPO	NM_000250.2 link	c.995C>T	p.Ala332Val	missense_variant	Exon 7 of 12	ENST00000225275.4	NP_000241.1	P05164-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MPO	ENST00000225275.4 link	c.995C>T	p.Ala332Val	missense_variant	Exon 7 of 12	1	NM_000250.2	ENSP00000225275.3	P05164-1
MPO	ENST00000578493.2 link	n.270C>T		non_coding_transcript_exon_variant	Exon 2 of 7	3
MPO	ENST00000699291.1 link	n.281C>T		non_coding_transcript_exon_variant	Exon 2 of 6			ENSP00000514272.1	A0A8V8TPE5

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

GnomAD2 exomes

AF:

0.0124

AC:

3112

AN:

250932

AF XY:

0.0122

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 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

African (AFR)

AF:

0.00248

AC:

AN:

33480

American (AMR)

AF:

0.00174

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00172

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0409

AC:

2161

AN:

52806

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0165

AC:

18356

AN:

1111998

Other (OTH)

AF:

0.00992

AC:

599

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

1420

2839

4259

5678

7098

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

676

1352

2028

2704

3380

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0112

AC:

1703

AN:

152358

Hom.:

Cov.:

AF XY:

0.0121

AC XY:

901

AN XY:

74512

show subpopulations

African (AFR)

AF:

0.00209

AC:

AN:

41594

American (AMR)

AF:

0.00281

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.0491

AC:

522

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0152

AC:

1036

AN:

68028

Other (OTH)

AF:

0.00378

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

158

237

316

395

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0115

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

May 28, 2019

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2004

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

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. -

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:curation

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. -

not provided

Benign:1

Oct 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

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

PhyloP100

4.1

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

Mutation Taster

=96/4

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over