17-58271761-T-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_000250.2(MPO):c.1924A>C(p.Ile642Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00413 in 1,614,050 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0031 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (19 hom.)
• Consequence: MPO NM_000250.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.48

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_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.026431352).
• BP6: Variant 17-58271761-T-G is Benign according to our data. Variant chr17-58271761-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 3052711.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MPO	NM_000250.2	c.1924A>C	p.Ile642Leu	missense_variant	11/12	ENST00000225275.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MPO	ENST00000225275.4	c.1924A>C	p.Ile642Leu	missense_variant	11/12	1	NM_000250.2	P1

Frequencies

GnomAD3 genomes AF: 0.00306 AC: 466 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00772

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00422

Gnomad OTH AF: 0.00623

GnomAD3 exomes AF: 0.00260 AC: 654 AN: 251270 Hom.: 1 AF XY: 0.00237 AC XY: 322 AN XY: 135880

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00390

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.00395

Gnomad OTH exome AF: 0.00587

GnomAD4 exome AF: 0.00424 AC: 6205 AN: 1461726 Hom.: 19 Cov.: 32 AF XY: 0.00412 AC XY: 2993 AN XY: 727176

Gnomad4 AFR exome AF: 0.000926

Gnomad4 AMR exome AF: 0.00438

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.000244

Gnomad4 NFE exome AF: 0.00512

Gnomad4 OTH exome AF: 0.00422

GnomAD4 genome AF: 0.00306 AC: 466 AN: 152324 Hom.: 0 Cov.: 32 AF XY: 0.00275 AC XY: 205 AN XY: 74488

Gnomad4 AFR AF: 0.00111

Gnomad4 AMR AF: 0.00771

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00422

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00413 Hom.: 2

Bravo AF: 0.00387

TwinsUK AF: 0.00539 AC: 20

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00337 AC: 29

ExAC AF: 0.00224 AC: 272

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00436

EpiControl AF: 0.00433

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

MPO-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 31, 2024

This variant is classified as likely 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	0.19
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	21
Dann	Uncertain	0.98
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.041
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.026	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	-0.20	N
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.20
Sift	Benign	0.13	T
Sift4G	Benign	0.66	T
Polyphen		0.25	B
Vest4		0.51
MVP		0.72
MPC		0.72
ClinPred		0.064	T
GERP RS		5.2
Varity_R		0.67
gMVP		0.59

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: rs112737382; hg19: chr17-56349122; COSMIC: COSV99031651; COSMIC: COSV99031651;