rs2234922

chr1-225838705-A-Gchr1-225838705-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001136018.4(EPHX1):c.416A>G(p.His139Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.201 in 1,613,876 control chromosomes in the GnomAD database, including 34,207 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.23 (4315 hom., cov: 32)
  • Exomes 𝑓: 0.20 (29892 hom.)
• Consequence: EPHX1 NM_001136018.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.840

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0043976605).
• BP6: Variant 1-225838705-A-G is Benign according to our data. Variant chr1-225838705-A-G is described in ClinVar as [Benign]. Clinvar id is 16605.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-225838705-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.334 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPHX1	NM_001136018.4	c.416A>G	p.His139Arg	missense_variant	4/9	ENST00000272167.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPHX1	ENST00000272167.10	c.416A>G	p.His139Arg	missense_variant	4/9	1	NM_001136018.4	P1
EPHX1	ENST00000366837.5	c.416A>G	p.His139Arg	missense_variant	4/9	1		P1
EPHX1	ENST00000614058.4	c.416A>G	p.His139Arg	missense_variant	4/9	1		P1
EPHX1	ENST00000448202.5			downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.226 AC: 34379 AN: 151902 Hom.: 4306 Cov.: 32

Gnomad AFR AF: 0.338

Gnomad AMI AF: 0.0965

Gnomad AMR AF: 0.159

Gnomad ASJ AF: 0.140

Gnomad EAS AF: 0.135

Gnomad SAS AF: 0.233

Gnomad FIN AF: 0.155

Gnomad MID AF: 0.194

Gnomad NFE AF: 0.198

Gnomad OTH AF: 0.207

GnomAD3 exomes AF: 0.187 AC: 47000 AN: 251356 Hom.: 4990 AF XY: 0.191 AC XY: 25898 AN XY: 135876

Gnomad AFR exome AF: 0.347

Gnomad AMR exome AF: 0.0937

Gnomad ASJ exome AF: 0.139

Gnomad EAS exome AF: 0.126

Gnomad SAS exome AF: 0.234

Gnomad FIN exome AF: 0.152

Gnomad NFE exome AF: 0.201

Gnomad OTH exome AF: 0.180

GnomAD4 exome AF: 0.198 AC: 289533 AN: 1461856 Hom.: 29892 Cov.: 37 AF XY: 0.199 AC XY: 144857 AN XY: 727232

Gnomad4 AFR exome AF: 0.344

Gnomad4 AMR exome AF: 0.0992

Gnomad4 ASJ exome AF: 0.143

Gnomad4 EAS exome AF: 0.147

Gnomad4 SAS exome AF: 0.233

Gnomad4 FIN exome AF: 0.161

Gnomad4 NFE exome AF: 0.200

Gnomad4 OTH exome AF: 0.193

GnomAD4 genome AF: 0.226 AC: 34426 AN: 152020 Hom.: 4315 Cov.: 32 AF XY: 0.221 AC XY: 16463 AN XY: 74332

Gnomad4 AFR AF: 0.338

Gnomad4 AMR AF: 0.158

Gnomad4 ASJ AF: 0.140

Gnomad4 EAS AF: 0.135

Gnomad4 SAS AF: 0.234

Gnomad4 FIN AF: 0.155

Gnomad4 NFE AF: 0.198

Gnomad4 OTH AF: 0.207

Alfa AF: 0.193 Hom.: 7043

Bravo AF: 0.229

TwinsUK AF: 0.200 AC: 742

ALSPAC AF: 0.202 AC: 779

ESP6500AA AF: 0.337 AC: 1484

ESP6500EA AF: 0.205 AC: 1763

ExAC AF: 0.196 AC: 23815

EpiCase AF: 0.191

EpiControl AF: 0.191

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

EPOXIDE HYDROLASE 1 POLYMORPHISM Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Sep 01, 2002

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 11, 2018

This variant is associated with the following publications: (PMID: 25087612, 19307236, 15535985, 21183608, 20091863, 18571762, 19952982, 21445251, 22928041, 23451147, 12173035, 20157331) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	1.9
Dann	Benign	0.49
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.022	T;.;T;.
MetaRNN	Benign	0.0044	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.76	N;N;.;N
REVEL	Benign	0.028
Sift	Benign	1.0	T;T;.;T
Sift4G	Benign	0.60	T;T;T;T
Polyphen		0.0	.;B;B;B
Vest4		0.011, 0.018, 0.012
MPC		0.24
ClinPred		0.00065	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.013
gMVP		0.32

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

Publications

LitVar

Other links and lift over

dbSNP: rs2234922; hg19: chr1-226026406; COSMIC: COSV55299484; COSMIC: COSV55299484;