rs7208693

chr17-58280457-C-Achr17-58280457-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000250.2(MPO):c.157G>T(p.Val53Phe) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0814 in 1,613,748 control chromosomes in the GnomAD database, including 6,252 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.11 (1082 hom., cov: 32)
  • Exomes 𝑓: 0.079 (5170 hom.)
• Consequence: MPO NM_000250.2 missense, splice_region
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0440

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0012850165).
• BP6: Variant 17-58280457-C-A is Benign according to our data. Variant chr17-58280457-C-A is described in ClinVar as [Benign]. Clinvar id is 3055447.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-58280457-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.179 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MPO	NM_000250.2	c.157G>T	p.Val53Phe	missense_variant, splice_region_variant	2/12	ENST00000225275.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MPO	ENST00000225275.4	c.157G>T	p.Val53Phe	missense_variant, splice_region_variant	2/12	1	NM_000250.2	P1
MPO	ENST00000580005.1	n.86G>T		splice_region_variant, non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes AF: 0.108 AC: 16466 AN: 152042 Hom.: 1078 Cov.: 32

Gnomad AFR AF: 0.183

Gnomad AMI AF: 0.0835

Gnomad AMR AF: 0.0679

Gnomad ASJ AF: 0.0297

Gnomad EAS AF: 0.117

Gnomad SAS AF: 0.0860

Gnomad FIN AF: 0.124

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0758

Gnomad OTH AF: 0.0860

GnomAD3 exomes AF: 0.0895 AC: 22421 AN: 250438 Hom.: 1208 AF XY: 0.0851 AC XY: 11528 AN XY: 135414

Gnomad AFR exome AF: 0.184

Gnomad AMR exome AF: 0.0855

Gnomad ASJ exome AF: 0.0331

Gnomad EAS exome AF: 0.125

Gnomad SAS exome AF: 0.0818

Gnomad FIN exome AF: 0.122

Gnomad NFE exome AF: 0.0732

Gnomad OTH exome AF: 0.0720

GnomAD4 exome AF: 0.0786 AC: 114847 AN: 1461586 Hom.: 5170 Cov.: 32 AF XY: 0.0775 AC XY: 56331 AN XY: 727084

Gnomad4 AFR exome AF: 0.190

Gnomad4 AMR exome AF: 0.0838

Gnomad4 ASJ exome AF: 0.0333

Gnomad4 EAS exome AF: 0.126

Gnomad4 SAS exome AF: 0.0789

Gnomad4 FIN exome AF: 0.119

Gnomad4 NFE exome AF: 0.0728

Gnomad4 OTH exome AF: 0.0765

GnomAD4 genome AF: 0.108 AC: 16491 AN: 152162 Hom.: 1082 Cov.: 32 AF XY: 0.109 AC XY: 8136 AN XY: 74376

Gnomad4 AFR AF: 0.183

Gnomad4 AMR AF: 0.0686

Gnomad4 ASJ AF: 0.0297

Gnomad4 EAS AF: 0.118

Gnomad4 SAS AF: 0.0859

Gnomad4 FIN AF: 0.124

Gnomad4 NFE AF: 0.0758

Gnomad4 OTH AF: 0.0865

Alfa AF: 0.0709 Hom.: 956

Bravo AF: 0.108

TwinsUK AF: 0.0750 AC: 278

ALSPAC AF: 0.0714 AC: 275

ESP6500AA AF: 0.184 AC: 812

ESP6500EA AF: 0.0726 AC: 624

ExAC AF: 0.0913 AC: 11080

Asia WGS AF: 0.114 AC: 395 AN: 3478

EpiCase AF: 0.0604

EpiControl AF: 0.0639

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

MPO-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 02, 2020

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	Benign	0.074
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	3.8
Dann	Benign	0.97
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.27	T
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.072
Sift	Benign	0.25	T
Sift4G	Benign	0.45	T
Polyphen		0.086	B
Vest4		0.12
MPC		0.46
ClinPred		0.0018	T
GERP RS		-1.8
Varity_R		0.077
gMVP		0.43

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: rs7208693; hg19: chr17-56357818; COSMIC: COSV56563158; COSMIC: COSV56563158;