17-58270745-T-C

Variant names:

• chr17-58270745-T-C
• rs2759
• NM_000250.2:c.2149A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong 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. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 28 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004686773).
• 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 rank	MANE	Protein	UniProt
MPO	NM_000250.2	c.2149A>G	p.Ile717Val	missense_variant	Exon 12 of 12	ENST00000225275.4	NP_000241.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MPO	ENST00000225275.4	c.2149A>G	p.Ile717Val	missense_variant	Exon 12 of 12	1	NM_000250.2	ENSP00000225275.3

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

GnomAD2 exomes AF: 0.0237 AC: 5942 AN: 251204 AF XY: 0.0240

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 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

African (AFR) AF: 0.0113 AC: 379 AN: 33478

American (AMR) AF: 0.0186 AC: 832 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0623 AC: 1629 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0164 AC: 1417 AN: 86254

European-Finnish (FIN) AF: 0.0302 AC: 1611 AN: 53416

Middle Eastern (MID) AF: 0.0581 AC: 335 AN: 5768

European-Non Finnish (NFE) AF: 0.0253 AC: 28082 AN: 1111970

Other (OTH) AF: 0.0265 AC: 1600 AN: 60394

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

African (AFR) AF: 0.0109 AC: 453 AN: 41502

American (AMR) AF: 0.0190 AC: 290 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0565 AC: 196 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.0120 AC: 58 AN: 4818

European-Finnish (FIN) AF: 0.0294 AC: 312 AN: 10608

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0268 AC: 1824 AN: 67990

Other (OTH) AF: 0.0265 AC: 56 AN: 2112

Alfa AF: 0.0257 Hom.: 240

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;.
PhyloP100		0.39
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
Mutation Taster		=94/6	polymorphism (auto)

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

Other links and lift over

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