rs28730837

chr17-58278036-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:2
• Conservation: PhyloP100: 4.13

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 -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 GnomAd at 31 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MPO	NM_000250.2	c.995C>T	p.Ala332Val	missense_variant	7/12	ENST00000225275.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MPO	ENST00000225275.4	c.995C>T	p.Ala332Val	missense_variant	7/12	1	NM_000250.2	P1
MPO	ENST00000578493.2	n.270C>T		non_coding_transcript_exon_variant	2/7	3
MPO	ENST00000699291.1	c.281C>T	p.Ala94Val	missense_variant, NMD_transcript_variant	2/6

Frequencies

GnomAD3 genomes AF: 0.0112 AC: 1703 AN: 152240 Hom.: 31 Cov.: 32

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.: 41 AF XY: 0.0122 AC XY: 1657 AN XY: 135680

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.: 32 AF XY: 0.0141 AC XY: 10245 AN XY: 726956

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.: 31 Cov.: 32 AF XY: 0.0121 AC XY: 901 AN XY: 74512

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.: 10

Bravo AF: 0.00818

TwinsUK AF: 0.0132 AC: 49

ALSPAC AF: 0.0174 AC: 67

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.0135 AC: 116

ExAC AF: 0.0132 AC: 1609

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0140

EpiControl AF: 0.0126

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Myeloperoxidase deficiency Pathogenic:1 Uncertain:2 Benign:1

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	- -
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. -

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	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	0.98	A;A
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.21
Sift	Benign	0.084	T
Sift4G	Uncertain	0.059	T
Polyphen		0.89	P
Vest4		0.10
MPC		0.41
ClinPred		0.020	T
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

Other links and lift over

dbSNP: rs28730837; hg19: chr17-56355397; COSMIC: COSV56567824; COSMIC: COSV56567824;