dbSNP rs35897051: MPO:c.2031-2A>C (chr17-58270865-T-G) – ACMG Classification: Pathogenic (13 pts)

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PVS1PS3PP5

The NM_000250.2(MPO):c.2031-2A>C variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00554 in 1,612,874 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000221199: Functional studies indicate that this variant leads to altered splicing (Marchetti 2004).".

Frequency

Genomes: 𝑓 0.0046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0056 ( 25 hom. )

Consequence

MPO
NM_000250.2 splice_acceptor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:21U:1O:1

Conservation

PhyloP100: 8.01

Publications

31 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: Pathogenic. The variant received 13 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease,

PS3

PS3 evidence extracted from ClinVar submissions: SCV000221199: Functional studies indicate that this variant leads to altered splicing (Marchetti 2004).

PP5

Variant 17-58270865-T-G is Pathogenic according to our data. Variant chr17-58270865-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3632.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MPO	NM_000250.2	MANE Select	c.2031-2A>C		splice_acceptor intron	N/A	NP_000241.1	P05164-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MPO	ENST00000225275.4	TSL:1 MANE Select	c.2031-2A>C	splice_acceptor intron	N/A	ENSP00000225275.3	P05164-1
MPO	ENST00000577220.1	TSL:3	c.184-60A>C	intron	N/A	ENSP00000464668.1	J3QSF7
MPO	ENST00000578493.2	TSL:3	n.1364-2A>C	splice_acceptor intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00456

AC:

693

AN:

152044

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00116

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.00576

Gnomad ASJ

AF:

0.0150

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00132

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00703

Gnomad OTH

AF:

0.00526

GnomAD2 exomes

AF:

0.00437

AC:

1098

AN:

251174

AF XY:

0.00411

show subpopulations

Gnomad AFR exome

AF:

0.000862

Gnomad AMR exome

AF:

0.00283

Gnomad ASJ exome

AF:

0.0121

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00171

Gnomad NFE exome

AF:

0.00715

Gnomad OTH exome

AF:

0.00196

GnomAD4 exome

AF:

0.00565

AC:

8250

AN:

1460712

Hom.:

Cov.:

AF XY:

0.00550

AC XY:

3999

AN XY:

726678

show subpopulations

African (AFR)

AF:

0.000628

AC:

AN:

33436

American (AMR)

AF:

0.00266

AC:

119

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0129

AC:

336

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.000128

AC:

AN:

86204

European-Finnish (FIN)

AF:

0.00247

AC:

132

AN:

53418

Middle Eastern (MID)

AF:

0.00145

AC:

AN:

4816

European-Non Finnish (NFE)

AF:

0.00659

AC:

7330

AN:

1111988

Other (OTH)

AF:

0.00486

AC:

293

AN:

60290

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

467

934

1401

1868

2335

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

260

520

780

1040

1300

<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:

0.00455

AC:

693

AN:

152162

Hom.:

Cov.:

AF XY:

0.00413

AC XY:

307

AN XY:

74386

show subpopulations

African (AFR)

AF:

0.00116

AC:

AN:

41494

American (AMR)

AF:

0.00575

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0150

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00132

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00703

AC:

478

AN:

67990

Other (OTH)

AF:

0.00521

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

102

136

170

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00608

Hom.:

Bravo

AF:

0.00400

TwinsUK

AF:

0.00755

AC:

ALSPAC

AF:

0.00649

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00721

AC:

ExAC

AF:

0.00424

AC:

515

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00600

EpiControl

AF:

0.00557

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Myeloperoxidase deficiency (12)

not provided (8)

MPO-related disorder (1)

Myeloperoxidase deficiency;C1863052:Alzheimer disease type 1 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.94

FATHMM_MKL

Uncertain

0.96

PhyloP100

8.0

GERP RS

5.4

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.98

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.98

Position offset: -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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over