17-58193513-C-A

Position:

• chr17-58193513-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000502.6(EPX):​c.313C>A​(p.Gln105Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EPX NM_000502.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.02

Genes affected

EPX (HGNC:3423): (eosinophil peroxidase) This gene is a member of the peroxidase gene family and is expressed in eosinophils. The encoded preproprotein is proteolytically processed into covalently attached heavy and light chains to form the mature enzyme, which functions as an oxidant. The enzyme is released at sites of parasitic infection or allergen stimulation to mediate lysis of protozoa or parasitic worms. The gene is found in a gene cluster with other peroxidase genes on chromosome 17. Mutations in this gene result in eosinophil peroxidase deficiency. [provided by RefSeq, Feb 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1409812).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPX	NM_000502.6	c.313C>A	p.Gln105Lys	missense_variant	3/13	ENST00000225371.6	NP_000493.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPX	ENST00000225371.6	c.313C>A	p.Gln105Lys	missense_variant	3/13	2	NM_000502.6	ENSP00000225371	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251364 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135844

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 2022

The c.313C>A (p.Q105K) alteration is located in exon 3 (coding exon 3) of the EPX gene. This alteration results from a C to A substitution at nucleotide position 313, causing the glutamine (Q) at amino acid position 105 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	15
DANN	Benign	0.52
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.80	N
REVEL	Benign	0.10
Sift	Benign	0.56	T
Sift4G	Benign	1.0	T
Polyphen		0.012	B
Vest4		0.33
MutPred		0.35		Gain of ubiquitination at Q105 (P = 0.0101);
MVP		0.58
MPC		0.15
ClinPred		0.95	D
GERP RS		3.4
Varity_R		0.16
gMVP		0.64

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

Publications

LitVar

Other links and lift over

dbSNP: rs750729437; hg19: chr17-56270874;