17-58193064-G-A

Variant names:

• chr17-58193064-G-A
• rs34553736
• NM_000502.6:c.103G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000502.6(EPX):​c.103G>A​(p.Val35Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000796 in 1,613,374 control chromosomes in the GnomAD database, including 14 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0042 (9 hom., cov: 32)
  • Exomes 𝑓: 0.00044 (5 hom.)
• Consequence: EPX NM_000502.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.21
• Publications: 3 publications found

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]

EPX Gene-Disease associations (from GenCC):

• eosinophil peroxidase deficiency

  Inheritance: AR Classification: NO_KNOWN Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006103128).
• BP6: Variant 17-58193064-G-A is Benign according to our data. Variant chr17-58193064-G-A is described in ClinVar as Benign. ClinVar VariationId is 720759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000502.6. 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
	EPX	NM_000502.6	MANE Select	c.103G>A	p.Val35Ile	missense	Exon 2 of 13	NP_000493.1	P11678

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPX	ENST00000225371.6	TSL:2 MANE Select	c.103G>A	p.Val35Ile	missense	Exon 2 of 13	ENSP00000225371.5	P11678

Frequencies

GnomAD3 genomes AF: 0.00422 AC: 642 AN: 152162 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.0147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00118 AC: 298 AN: 251482 AF XY: 0.000942

Gnomad AFR exome AF: 0.0155

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000437 AC: 639 AN: 1461094 Hom.: 5 Cov.: 31 AF XY: 0.000369 AC XY: 268 AN XY: 726962

African (AFR) AF: 0.0144 AC: 483 AN: 33474

American (AMR) AF: 0.00123 AC: 55 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.0000270 AC: 30 AN: 1111260

Other (OTH) AF: 0.00101 AC: 61 AN: 60378

GnomAD4 genome AF: 0.00424 AC: 646 AN: 152280 Hom.: 9 Cov.: 32 AF XY: 0.00400 AC XY: 298 AN XY: 74472

African (AFR) AF: 0.0147 AC: 612 AN: 41548

American (AMR) AF: 0.00183 AC: 28 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68010

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00180 Hom.: 4

Bravo AF: 0.00505

ESP6500AA AF: 0.0104 AC: 46

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00139 AC: 169

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	14
DANN	Benign	0.97
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.50	T
MetaRNN	Benign	0.0061	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		2.2
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.0	N
REVEL	Benign	0.16
Sift	Benign	0.59	T
Sift4G	Benign	0.45	T
Polyphen		0.038	B
Vest4		0.12
MVP		0.56
MPC		0.10
ClinPred		0.027	T
GERP RS		5.1
PromoterAI		0.013	Neutral
Varity_R		0.031
gMVP		0.18
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs34553736; hg19: chr17-56270425;