1-225831799-T-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_001136018.4(EPHX1):c.204T>C(p.Asp68=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0181 in 1,614,094 control chromosomes in the GnomAD database, including 321 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.012 (18 hom., cov: 32)
  • Exomes 𝑓: 0.019 (303 hom.)
• Consequence: EPHX1 NM_001136018.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.19

Genes affected

EPHX1 (HGNC:3401): (epoxide hydrolase 1) Epoxide hydrolase is a critical biotransformation enzyme that converts epoxides from the degradation of aromatic compounds to trans-dihydrodiols which can be conjugated and excreted from the body. Epoxide hydrolase functions in both the activation and detoxification of epoxides. Mutations in this gene cause preeclampsia, epoxide hydrolase deficiency or increased epoxide hydrolase activity. Alternatively spliced transcript variants encoding the same protein have been found for this gene.[provided by RefSeq, Dec 2008]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 1-225831799-T-C is Benign according to our data. Variant chr1-225831799-T-C is described in ClinVar as [Benign]. Clinvar id is 3037613.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.19 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0119 (1819/152266) while in subpopulation NFE AF= 0.0199 (1355/68022). AF 95% confidence interval is 0.019. There are 18 homozygotes in gnomad4. There are 791 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPHX1	NM_001136018.4	c.204T>C	p.Asp68=	synonymous_variant	3/9	ENST00000272167.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPHX1	ENST00000272167.10	c.204T>C	p.Asp68=	synonymous_variant	3/9	1	NM_001136018.4	P1

Frequencies

GnomAD3 genomes AF: 0.0119 AC: 1818 AN: 152148 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.00369

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.00923

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00725

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0199

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.0116 AC: 2911 AN: 251488 Hom.: 21 AF XY: 0.0117 AC XY: 1589 AN XY: 135922

Gnomad AFR exome AF: 0.00283

Gnomad AMR exome AF: 0.00558

Gnomad ASJ exome AF: 0.00228

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00363

Gnomad FIN exome AF: 0.00725

Gnomad NFE exome AF: 0.0202

Gnomad OTH exome AF: 0.0134

GnomAD4 exome AF: 0.0187 AC: 27329 AN: 1461828 Hom.: 303 Cov.: 32 AF XY: 0.0181 AC XY: 13175 AN XY: 727222

Gnomad4 AFR exome AF: 0.00257

Gnomad4 AMR exome AF: 0.00595

Gnomad4 ASJ exome AF: 0.00203

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00370

Gnomad4 FIN exome AF: 0.00758

Gnomad4 NFE exome AF: 0.0228

Gnomad4 OTH exome AF: 0.0130

GnomAD4 genome AF: 0.0119 AC: 1819 AN: 152266 Hom.: 18 Cov.: 32 AF XY: 0.0106 AC XY: 791 AN XY: 74452

Gnomad4 AFR AF: 0.00368

Gnomad4 AMR AF: 0.00922

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.00725

Gnomad4 NFE AF: 0.0199

Gnomad4 OTH AF: 0.0119

Alfa AF: 0.0180 Hom.: 80

Bravo AF: 0.0120

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0183

EpiControl AF: 0.0188

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

EPHX1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 16, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	1.3
Dann	Benign	0.45
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs2234698; hg19: chr1-226019500;