17-58195171-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 3P and 12B. PVS1_Moderate PP3 BP6_Very_Strong BS2

The NM_000502.6(EPX):c.801+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00258 in 1,612,606 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (10 hom.)
• Consequence: EPX NM_000502.6 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 9.56

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 Benign. Variant got -9 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.095903166 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PP3: Multiple lines of computational evidence support a deleterious effect 6: Cadd, dbscSNV1_ADA, dbscSNV1_RF, max_spliceai, Eigen, phyloP100way_vertebrate [when BayesDel_addAF, MutationTaster was below the threshold]
• BP6: Variant 17-58195171-G-A is Benign according to our data. Variant chr17-58195171-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 779025.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPX	NM_000502.6	c.801+1G>A		splice_donor_variant		ENST00000225371.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPX	ENST00000225371.6	c.801+1G>A		splice_donor_variant		2	NM_000502.6	P1

Frequencies

GnomAD3 genomes AF: 0.00192 AC: 292 AN: 152156 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00264

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00293

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00186 AC: 466 AN: 251146 Hom.: 1 AF XY: 0.00194 AC XY: 264 AN XY: 135742

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00180

Gnomad FIN exome AF: 0.00186

Gnomad NFE exome AF: 0.00265

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00265 AC: 3866 AN: 1460332 Hom.: 10 Cov.: 33 AF XY: 0.00265 AC XY: 1923 AN XY: 726576

Gnomad4 AFR exome AF: 0.00158

Gnomad4 AMR exome AF: 0.00161

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00215

Gnomad4 FIN exome AF: 0.00208

Gnomad4 NFE exome AF: 0.00292

Gnomad4 OTH exome AF: 0.00257

GnomAD4 genome AF: 0.00192 AC: 292 AN: 152274 Hom.: 2 Cov.: 32 AF XY: 0.00180 AC XY: 134 AN XY: 74446

Gnomad4 AFR AF: 0.000578

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00264

Gnomad4 NFE AF: 0.00293

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00224 Hom.: 1

Bravo AF: 0.00177

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00372 AC: 32

ExAC AF: 0.00196 AC: 238

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00262

EpiControl AF: 0.00326

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

May 23, 2018

- -

Eosinophil peroxidase deficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.066	T
BayesDel_noAF	Uncertain	0.13
Cadd	Pathogenic	35
Dann	Uncertain	0.98
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	D
GERP RS		3.4

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.71		Position offset: -45
DS_DL_spliceai		1.0		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs34599426; hg19: chr17-56272532;