rs2759

Positions:

• chr17-58270745-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_000250.2(MPO):​c.2149A>G​(p.Ile717Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0242 in 1,614,018 control chromosomes in the GnomAD database, including 546 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in Lovd as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.021 (42 hom., cov: 32)
  • Exomes 𝑓: 0.025 (504 hom.)
• Consequence: MPO NM_000250.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.390

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004686773).
• BP6: Variant 17-58270745-T-C is Benign according to our data. Variant chr17-58270745-T-C is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.053 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MPO	NM_000250.2	c.2149A>G	p.Ile717Val	missense_variant	12/12	ENST00000225275.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MPO	ENST00000225275.4	c.2149A>G	p.Ile717Val	missense_variant	12/12	1	NM_000250.2	P1

Frequencies

GnomAD3 genomes AF: 0.0211 AC: 3210 AN: 152060 Hom.: 42 Cov.: 32

Gnomad AFR AF: 0.0109

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0189

Gnomad ASJ AF: 0.0565

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0120

Gnomad FIN AF: 0.0294

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0268

Gnomad OTH AF: 0.0268

GnomAD3 exomes AF: 0.0237 AC: 5942 AN: 251204 Hom.: 85 AF XY: 0.0240 AC XY: 3259 AN XY: 135862

Gnomad AFR exome AF: 0.0107

Gnomad AMR exome AF: 0.0172

Gnomad ASJ exome AF: 0.0641

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0160

Gnomad FIN exome AF: 0.0278

Gnomad NFE exome AF: 0.0283

Gnomad OTH exome AF: 0.0369

GnomAD4 exome AF: 0.0245 AC: 35887 AN: 1461840 Hom.: 504 Cov.: 30 AF XY: 0.0245 AC XY: 17817 AN XY: 727222

Gnomad4 AFR exome AF: 0.0113

Gnomad4 AMR exome AF: 0.0186

Gnomad4 ASJ exome AF: 0.0623

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0164

Gnomad4 FIN exome AF: 0.0302

Gnomad4 NFE exome AF: 0.0253

Gnomad4 OTH exome AF: 0.0265

GnomAD4 genome AF: 0.0211 AC: 3211 AN: 152178 Hom.: 42 Cov.: 32 AF XY: 0.0210 AC XY: 1564 AN XY: 74398

Gnomad4 AFR AF: 0.0109

Gnomad4 AMR AF: 0.0190

Gnomad4 ASJ AF: 0.0565

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0120

Gnomad4 FIN AF: 0.0294

Gnomad4 NFE AF: 0.0268

Gnomad4 OTH AF: 0.0265

Alfa AF: 0.0268 Hom.: 140

Bravo AF: 0.0206

TwinsUK AF: 0.0264 AC: 98

ALSPAC AF: 0.0262 AC: 101

ESP6500AA AF: 0.0109 AC: 48

ESP6500EA AF: 0.0286 AC: 246

ExAC AF: 0.0245 AC: 2977

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.0270

EpiControl AF: 0.0275

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	17
DANN	Benign	0.94
DEOGEN2	Benign	0.23	T;T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.67	T;T
MetaRNN	Benign	0.0047	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.11	N;.
MutationTaster	Benign	0.99	D;D
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.010	N;.
REVEL	Benign	0.11
Sift	Benign	1.0	T;.
Sift4G	Benign	0.92	T;.
Polyphen		0.12	B;.
Vest4		0.013
MPC		0.34
ClinPred		0.014	T
GERP RS		4.2
Varity_R		0.24
gMVP		0.50

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: rs2759; hg19: chr17-56348106; COSMIC: COSV51858135; COSMIC: COSV51858135;