17-58270847-C-G

Position:

chr17-58270847-C-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBS2_Supporting

The NM_000250.2(MPO):c.2047G>C(p.Glu683Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000477 in 1,613,310 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.0025 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00027 ( 5 hom. )

Consequence

MPO
NM_000250.2 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: -0.618

Variant links:

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]

MPO links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0042060018).

BS2

High Homozygotes in GnomAdExome4 at 5 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MPO	NM_000250.2 linkuse as main transcript	c.2047G>C	p.Glu683Gln	missense_variant	12/12	ENST00000225275.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MPO	ENST00000225275.4 linkuse as main transcript	c.2047G>C	p.Glu683Gln	missense_variant	12/12	1	NM_000250.2	P1	P05164-1

Frequencies

GnomAD3 genomes

AF:

0.00246

AC:

374

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00874

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000613

AC:

154

AN:

251266

Hom.:

AF XY:

0.000405

AC XY:

AN XY:

135876

show subpopulations

Gnomad AFR exome

AF:

0.00837

Gnomad AMR exome

AF:

0.000434

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000271

AC:

396

AN:

1461012

Hom.:

Cov.:

AF XY:

0.000222

AC XY:

161

AN XY:

726818

show subpopulations

Gnomad4 AFR exome

AF:

0.00981

Gnomad4 AMR exome

AF:

0.000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000719

Gnomad4 OTH exome

AF:

0.000630

GnomAD4 genome

AF:

0.00246

AC:

374

AN:

152298

Hom.:

Cov.:

AF XY:

0.00226

AC XY:

168

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.00871

Gnomad4 AMR

AF:

0.000588

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000134

Hom.:

Bravo

AF:

0.00273

ESP6500AA

AF:

0.00794

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000700

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The MPO p.E683Q variant was not identified in the literature nor was it identified in ClinVar or LOVD 3.0. The variant was identified in dbSNP (ID: rs35702888) and in control databases in 234 of 282640 chromosomes (1 homozygous) at a frequency of 0.0008279 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: African in 213 of 24936 chromosomes (freq: 0.008542), Other in 4 of 7220 chromosomes (freq: 0.000554), Latino in 15 of 35440 chromosomes (freq: 0.000423) and European (non-Finnish) in 2 of 128998 chromosomes (freq: 0.000016), but was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), or South Asian populations. The p.Glu683 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and one of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.55

CADD

Benign

4.8

DANN

Benign

0.78

DEOGEN2

Benign

0.21

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.068

LIST_S2

Benign

0.25

M_CAP

Benign

0.015

MetaRNN

Benign

0.0042

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.20

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.24

PROVEAN

Benign

0.020

REVEL

Benign

0.14

Sift

Benign

0.13

Sift4G

Benign

0.12

Polyphen

0.0

Vest4

0.036

MVP

0.37

MPC

0.34

ClinPred

0.0011

GERP RS

-5.5

Varity_R

0.27

gMVP

0.54

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over