Genetic Variant EPHX1:p.Arg49Cys (chr1-225828874-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_001136018.4(EPHX1):c.145C>T(p.Arg49Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00106 in 1,600,110 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0058 ( 10 hom., cov: 31)

Exomes 𝑓: 0.00056 ( 8 hom. )

Consequence

EPHX1
NM_001136018.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.763

Publications

11 publications found

Variant links:

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: Unknown Classification: LIMITED Submitted by: ClinGen

EPHX1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0116193).

BP6

Variant 1-225828874-C-T is Benign according to our data. Variant chr1-225828874-C-T is described in ClinVar as Benign. ClinVar VariationId is 786997.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00582 (881/151370) while in subpopulation AFR AF = 0.0204 (839/41170). AF 95% confidence interval is 0.0192. There are 10 homozygotes in GnomAd4. There are 408 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 10 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001136018.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EPHX1	NM_001136018.4	MANE Select	c.145C>T	p.Arg49Cys	missense	Exon 2 of 9	NP_001129490.1	R4SBI6
EPHX1	NM_000120.4		c.145C>T	p.Arg49Cys	missense	Exon 2 of 9	NP_000111.1	R4SBI6
EPHX1	NM_001291163.2		c.145C>T	p.Arg49Cys	missense	Exon 2 of 9	NP_001278092.1	P07099

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EPHX1	ENST00000272167.10	TSL:1 MANE Select	c.145C>T	p.Arg49Cys	missense	Exon 2 of 9	ENSP00000272167.5	P07099
EPHX1	ENST00000366837.5	TSL:1	c.145C>T	p.Arg49Cys	missense	Exon 2 of 9	ENSP00000355802.4	P07099
EPHX1	ENST00000614058.4	TSL:1	c.145C>T	p.Arg49Cys	missense	Exon 2 of 9	ENSP00000480004.1	P07099

Frequencies

GnomAD3 genomes

AF:

0.00580

AC:

877

AN:

151246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0203

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00211

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:

0.0000442

Gnomad OTH

AF:

0.00338

GnomAD2 exomes

AF:

0.00144

AC:

326

AN:

226284

AF XY:

0.00107

show subpopulations

Gnomad AFR exome

AF:

0.0190

Gnomad AMR exome

AF:

0.00138

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000608

Gnomad OTH exome

AF:

0.000707

GnomAD4 exome

AF:

0.000565

AC:

818

AN:

1448740

Hom.:

Cov.:

AF XY:

0.000495

AC XY:

356

AN XY:

719386

show subpopulations

African (AFR)

AF:

0.0193

AC:

643

AN:

33278

American (AMR)

AF:

0.00155

AC:

AN:

43318

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25768

East Asian (EAS)

AF:

0.0000506

AC:

AN:

39510

South Asian (SAS)

AF:

0.0000354

AC:

AN:

84712

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52574

Middle Eastern (MID)

AF:

0.000705

AC:

AN:

5674

European-Non Finnish (NFE)

AF:

0.0000254

AC:

AN:

1104102

Other (OTH)

AF:

0.00119

AC:

AN:

59804

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

100

149

199

249

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00582

AC:

881

AN:

151370

Hom.:

Cov.:

AF XY:

0.00552

AC XY:

408

AN XY:

73936

show subpopulations

African (AFR)

AF:

0.0204

AC:

839

AN:

41170

American (AMR)

AF:

0.00211

AC:

AN:

15190

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5088

South Asian (SAS)

AF:

0.00

AC:

AN:

4788

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10484

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0000442

AC:

AN:

67884

Other (OTH)

AF:

0.00334

AC:

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

118

157

196

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00188

Hom.:

Bravo

AF:

0.00662

ESP6500AA

AF:

0.0177

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00160

AC:

194

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.40

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.89

MetaRNN

Benign

0.012

MetaSVM

Benign

-0.53

MutationAssessor

Pathogenic

3.5

PhyloP100

0.76

PrimateAI

Benign

0.22

PROVEAN

Pathogenic

-5.4

REVEL

Benign

0.22

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.0020

Polyphen

0.99

Vest4

0.20

MVP

0.50

MPC

0.29

ClinPred

0.051

GERP RS

5.0

Varity_R

0.37

gMVP

0.67

Mutation Taster

=93/7

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over