17-58279141-A-T

Variant names:

• chr17-58279141-A-T
• rs56378716
• NM_000250.2:c.752T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000250.2(MPO):​c.752T>A​(p.Met251Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M251T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MPO NM_000250.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.50
• Publications: 0 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.966

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MPO	NM_000250.2	c.752T>A	p.Met251Lys	missense_variant	Exon 6 of 12	ENST00000225275.4	NP_000241.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MPO	ENST00000225275.4	c.752T>A	p.Met251Lys	missense_variant	Exon 6 of 12	1	NM_000250.2	ENSP00000225275.3
MPO	ENST00000578493.2	n.27T>A		non_coding_transcript_exon_variant	Exon 1 of 7	3
MPO	ENST00000581022.1	n.177T>A		non_coding_transcript_exon_variant	Exon 2 of 2	2
MPO	ENST00000699291.1	n.38T>A		non_coding_transcript_exon_variant	Exon 1 of 6			ENSP00000514272.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.84	D
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.80	T
M_CAP	Uncertain	0.090	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Pathogenic	3.5	M
PhyloP100		7.5
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.070	T
Polyphen		0.032	B
Vest4		0.92
MutPred		0.85		Gain of ubiquitination at M251 (P = 0.0289);
MVP		0.93
MPC		0.59
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.98
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs56378716; hg19: chr17-56356502;