rs56378716

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr17-58279141-A-G
• chr17-58279141-A-T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000250.2(MPO):​c.752T>C​(p.Met251Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0115 in 1,612,960 control chromosomes in the GnomAD database, including 147 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0095 (14 hom., cov: 32)
  • Exomes 𝑓: 0.012 (133 hom.)
• Consequence: MPO NM_000250.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:4
• Conservation: PhyloP100: 7.50
• Publications: 36 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010124564).
• BP6: Variant 17-58279141-A-G is Benign according to our data. Variant chr17-58279141-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3628.
• BS2: High Homozygotes in GnomAd4 at 14 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000250.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MPO	NM_000250.2	MANE Select	c.752T>C	p.Met251Thr	missense	Exon 6 of 12	NP_000241.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MPO	ENST00000225275.4	TSL:1 MANE Select	c.752T>C	p.Met251Thr	missense	Exon 6 of 12	ENSP00000225275.3
	MPO	ENST00000578493.2	TSL:3	n.27T>C		non_coding_transcript_exon	Exon 1 of 7
	MPO	ENST00000581022.1	TSL:2	n.177T>C		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.00949 AC: 1444 AN: 152212 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.00215

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00530

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.0343

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0126

Gnomad OTH AF: 0.00860

GnomAD2 exomes AF: 0.0102 AC: 2529 AN: 247036 AF XY: 0.00999

Gnomad AFR exome AF: 0.00172

Gnomad AMR exome AF: 0.00336

Gnomad ASJ exome AF: 0.0104

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0318

Gnomad NFE exome AF: 0.0135

Gnomad OTH exome AF: 0.00960

GnomAD4 exome AF: 0.0117 AC: 17036 AN: 1460630 Hom.: 133 Cov.: 32 AF XY: 0.0112 AC XY: 8105 AN XY: 726494

African (AFR) AF: 0.00185 AC: 62 AN: 33470

American (AMR) AF: 0.00337 AC: 150 AN: 44556

Ashkenazi Jewish (ASJ) AF: 0.00954 AC: 249 AN: 26090

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39662

South Asian (SAS) AF: 0.00162 AC: 139 AN: 85960

European-Finnish (FIN) AF: 0.0339 AC: 1808 AN: 53270

Middle Eastern (MID) AF: 0.00434 AC: 25 AN: 5766

European-Non Finnish (NFE) AF: 0.0126 AC: 14043 AN: 1111512

Other (OTH) AF: 0.00926 AC: 559 AN: 60344

GnomAD4 genome AF: 0.00949 AC: 1445 AN: 152330 Hom.: 14 Cov.: 32 AF XY: 0.0102 AC XY: 760 AN XY: 74488

African (AFR) AF: 0.00214 AC: 89 AN: 41570

American (AMR) AF: 0.00529 AC: 81 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00778 AC: 27 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4830

European-Finnish (FIN) AF: 0.0343 AC: 364 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0126 AC: 858 AN: 68016

Other (OTH) AF: 0.00851 AC: 18 AN: 2116

Alfa AF: 0.0114 Hom.: 39

Bravo AF: 0.00723

TwinsUK AF: 0.0113 AC: 42

ALSPAC AF: 0.0138 AC: 53

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.0135 AC: 116

ExAC AF: 0.0101 AC: 1229

Asia WGS AF: 0.00173 AC: 7 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	2	-	Myeloperoxidase deficiency (3)
-	-	3	not provided (3)
-	-	1	MPO-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.71	D
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.44	T
MetaRNN	Benign	0.010	T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.5
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.032	B
Vest4		0.90
MPC		0.43
ClinPred		0.088	T
GERP RS		5.5
Varity_R		0.82
gMVP		0.82
Mutation Taster		=39/61	disease causing

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: rs56378716; hg19: chr17-56356502; COSMIC: COSV56563924; COSMIC: COSV56563924;