chr17-58270865-T-G

Position:

• chr17-58270865-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1 PP5

The ENST00000225275.4(MPO):​c.2031-2A>C variant causes a splice acceptor 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).

• Frequency:
  • Genomes: 𝑓 0.0046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0056 (25 hom.)
• Consequence: MPO ENST00000225275.4 splice_acceptor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:19 U:1 O:1
• Conservation: PhyloP100: 8.01

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 Likely_pathogenic. Variant got 9 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease,
• 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 id is 3632.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=5, Pathogenic=6, Uncertain_significance=1, not_provided=1}. Variant chr17-58270865-T-G is described in Lovd as [Pathogenic]. Variant chr17-58270865-T-G is described in Lovd as [Likely_pathogenic]. Variant chr17-58270865-T-G is described in Lovd as [Likely_pathogenic]. Variant chr17-58270865-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MPO	NM_000250.2	c.2031-2A>C		splice_acceptor_variant		ENST00000225275.4	NP_000241.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MPO	ENST00000225275.4	c.2031-2A>C		splice_acceptor_variant		1	NM_000250.2	ENSP00000225275	P1

Frequencies

GnomAD3 genomes AF: 0.00456 AC: 693 AN: 152044 Hom.: 0 Cov.: 32

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

GnomAD3 exomes AF: 0.00437 AC: 1098 AN: 251174 Hom.: 2 AF XY: 0.00411 AC XY: 558 AN XY: 135856

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 SAS exome AF: 0.0000980

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.: 25 Cov.: 31 AF XY: 0.00550 AC XY: 3999 AN XY: 726678

Gnomad4 AFR exome AF: 0.000628

Gnomad4 AMR exome AF: 0.00266

Gnomad4 ASJ exome AF: 0.0129

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00247

Gnomad4 NFE exome AF: 0.00659

Gnomad4 OTH exome AF: 0.00486

GnomAD4 genome AF: 0.00455 AC: 693 AN: 152162 Hom.: 0 Cov.: 32 AF XY: 0.00413 AC XY: 307 AN XY: 74386

Gnomad4 AFR AF: 0.00116

Gnomad4 AMR AF: 0.00575

Gnomad4 ASJ AF: 0.0150

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.00703

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00642 Hom.: 2

Bravo AF: 0.00400

TwinsUK AF: 0.00755 AC: 28

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00721 AC: 62

ExAC AF: 0.00424 AC: 515

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00600

EpiControl AF: 0.00557

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:19 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Myeloperoxidase deficiency Pathogenic:10 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2004	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 26, 2014	The 2031-2A>C variant in MPO has been previously identified in 1 compound heterozygous and 2 homozygous individuals with myeloperoxidase deficiency (Marchetti 2004). This variant is located in the 3' splice region and functional studies indicate that this variant leads to altered splicing (Marchetti 2004). In summary, the 2031-2A>C variant meets our criteria to be considered causative for myeloperoxidase deficiency (MPOD) in a recessive manner. However, the clinical relevance of MPOD is not well-established. -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinic of Clinical Immunology with Stem Cell Bank, Expert Centre for Rare Diseases - PID, University Hospital "Alexandrovska"	May 01, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Jul 08, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Payam Genetics Center, General Welfare Department of North Khorasan Province	Mar 01, 2023	- -
Pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NG_009629.1(NM_000250.1):c.2031-2A>C in the MPO gene has an allele frequency of 0.013 in Ashkenazi Jewish subpopulation in the gnomAD database. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. It was detected in individual with autosomal recessive Myeloperoxidase deficiency, compound heterozygous with c.1566_1579del14 (PMID:15108282). The patient's phenotype is highly specific for the MPO gene (PMID:15108282). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP criteria applied:PVS1; PM3; PP4; BS1. -
Pathogenic, no assertion criteria provided	clinical testing	Undiagnosed Diseases Network, NIH	May 22, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	This variant was identified as compound heterozygous. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 02, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -

not provided Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 16, 2024	Reported as a heterozygous germline variant in multiple individuals with myeloid neoplasms (PMID: 35761024); Splice site variant that destroys the canonical splice acceptor site in intron 11, and causes the activation of a cryptic splice site located 109 nucleotides upstream of the authentic splice site (PMID: 15108282); This variant is associated with the following publications: (PMID: 20974672, 25714468, 34662886, 35026467, 24385801, 17384005, 15108282, 26764160, 26822949, 27301573, 27827828, 30487145, 31980526, 32758448, 34426522, 32531373, 35761024, 36730508, 37868038, 38170104, 32758447) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	MPO: PM3, PS3:Moderate, PM2:Supporting, PP3 -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Mar 30, 2022	- -

Myeloperoxidase deficiency;C1863052:Alzheimer disease type 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 12, 2022

- -

MPO-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 05, 2024

The MPO c.2031-2A>C variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported to be causative for autosomal recessive myeloperoxidase deficiency (Marchetti et al. 2004. PubMed ID: 15108282; Vergnano et al. 2020. PubMed ID: 32758448). This variant is reported in 1.3% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. Variants that disrupt the consensus splice acceptor site in MPO are expected to be pathogenic, and this variant has been classified as pathogenic or likely pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/3632). This variant is interpreted as pathogenic. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 01, 2024

Variant summary: MPO c.2031-2A>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 3' acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing , and the predominant products were truncated MPO (Haskamp_2020), such mRNA products are not subject to NMD. The variant allele was found at a frequency of 0.0044 in 251174 control chromosomes in the gnomAD database, including 2 homozygotes (gnomAD v2), and in gnomAD v4 dataset, this vairant was found a frequency of 0.0066 in 1179978 control chromosomes in European (non-Finnish) group with 25 homozygotes, suggesting that the variant may be benign. c.2031-2A>C has been reported in the literature in at-least three individuals affected with Myeloperoxidase Deficiency (example, Marchetti_2004). Additionally, no pathogenic missense or in-frame changes from the last exon have been reported in ClinVar, suggesting the disrupted last exon may not be functionally important. The following publications have been ascertained in the context of this evaluation (PMID: 32758447, 15108282). ClinVar contains an entry for this variant (Variation ID: 3632). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	29
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Uncertain	0.96	D
MutationTaster	Benign	1.0	D;D
GERP RS		5.4

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

LitVar

Other links and lift over

dbSNP: rs35897051; hg19: chr17-56348226;