rs56378716

chr17-58279141-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:4
• Conservation: PhyloP100: 7.50

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

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010124564).
• BS2: High Homozygotes in GnomAd at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MPO	NM_000250.2	c.752T>C	p.Met251Thr	missense_variant	6/12	ENST00000225275.4

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00949 AC: 1444 AN: 152212 Hom.: 14 Cov.: 32

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.: 23 AF XY: 0.00999 AC XY: 1338 AN XY: 133968

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.: 32 AF XY: 0.0112 AC XY: 8105 AN XY: 726494

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.: 14 Cov.: 32 AF XY: 0.0102 AC XY: 760 AN XY: 74488

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.: 17

Bravo AF: 0.00723

TwinsUK AF: 0.0113 AC: 42

ALSPAC AF: 0.0138 AC: 53

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.0135 AC: 116

ExAC AF: 0.0101 AC: 1229

Asia WGS AF: 0.00173 AC: 7 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Myeloperoxidase deficiency Pathogenic:1 Uncertain: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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2004	- -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

MPO-related condition Benign:1

Benign, criteria provided, single submitter

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	T
BayesDel_noAF	Uncertain	-0.040
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.71	D
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.44	T
MetaRNN	Benign	0.010	T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.032	B
Vest4		0.90
MPC		0.43
ClinPred		0.088	T
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

Other links and lift over

dbSNP: rs56378716; hg19: chr17-56356502; COSMIC: COSV56563924; COSMIC: COSV56563924;