rs2234922

Variant names:

• chr1-225838705-A-G
• rs2234922
• NM_001136018.4:c.416A>G

Your query was ambiguous. Multiple possible variants found:

• chr1-225838705-A-G
• chr1-225838705-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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. 15/21 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, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.840
• Publications: 310 publications found

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]

EPHX1 Gene-Disease associations (from GenCC):

• familial hypercholanemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 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 VariationId is 16605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
EPHX1	NM_001136018.4	c.416A>G	p.His139Arg	missense_variant	Exon 4 of 9	ENST00000272167.10	NP_001129490.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPHX1	ENST00000272167.10	c.416A>G	p.His139Arg	missense_variant	Exon 4 of 9	1	NM_001136018.4	ENSP00000272167.5
EPHX1	ENST00000366837.5	c.416A>G	p.His139Arg	missense_variant	Exon 4 of 9	1		ENSP00000355802.4
EPHX1	ENST00000614058.4	c.416A>G	p.His139Arg	missense_variant	Exon 4 of 9	1		ENSP00000480004.1
EPHX1	ENST00000448202.5	c.*8A>G		downstream_gene_variant		2		ENSP00000408469.1

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

GnomAD2 exomes AF: 0.187 AC: 47000 AN: 251356 AF XY: 0.191

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 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

African (AFR) AF: 0.344 AC: 11524 AN: 33480

American (AMR) AF: 0.0992 AC: 4435 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.143 AC: 3739 AN: 26134

East Asian (EAS) AF: 0.147 AC: 5826 AN: 39700

South Asian (SAS) AF: 0.233 AC: 20077 AN: 86258

European-Finnish (FIN) AF: 0.161 AC: 8582 AN: 53416

Middle Eastern (MID) AF: 0.186 AC: 1070 AN: 5768

European-Non Finnish (NFE) AF: 0.200 AC: 222627 AN: 1111984

Other (OTH) AF: 0.193 AC: 11653 AN: 60394

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

African (AFR) AF: 0.338 AC: 14021 AN: 41446

American (AMR) AF: 0.158 AC: 2422 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 485 AN: 3470

East Asian (EAS) AF: 0.135 AC: 699 AN: 5162

South Asian (SAS) AF: 0.234 AC: 1126 AN: 4814

European-Finnish (FIN) AF: 0.155 AC: 1639 AN: 10590

Middle Eastern (MID) AF: 0.188 AC: 55 AN: 292

European-Non Finnish (NFE) AF: 0.198 AC: 13455 AN: 67940

Other (OTH) AF: 0.207 AC: 436 AN: 2110

Alfa AF: 0.202 Hom.: 15667

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

EPOXIDE HYDROLASE 1 POLYMORPHISM Benign:1

Sep 01, 2002

OMIM

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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
DEOGEN2	Benign	0.033	.;T;T;T
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
MutationAssessor	Benign	0.0	.;N;N;N
PhyloP100		0.84
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
Mutation Taster		=98/2	polymorphism (auto)

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