Genetic Variant EPHX1:p.Pro284Pro (chr1-225839958-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001136018.4(EPHX1):c.852C>T(p.Pro284Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0467 in 1,614,140 control chromosomes in the GnomAD database, including 2,264 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.046 ( 227 hom., cov: 32)

Exomes 𝑓: 0.047 ( 2037 hom. )

Consequence

EPHX1
NM_001136018.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.0660

Publications

18 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: AD 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.68).

BP6

Variant 1-225839958-C-T is Benign according to our data. Variant chr1-225839958-C-T is described in ClinVar as Benign. ClinVar VariationId is 1295081.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.136 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPHX1	NM_001136018.4 link	c.852C>T	p.Pro284Pro	synonymous_variant	Exon 6 of 9	ENST00000272167.10	NP_001129490.1	P07099R4SBI6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EPHX1	ENST00000272167.10 link	c.852C>T	p.Pro284Pro	synonymous_variant	Exon 6 of 9	1	NM_001136018.4	ENSP00000272167.5	P07099
EPHX1	ENST00000366837.5 link	c.852C>T	p.Pro284Pro	synonymous_variant	Exon 6 of 9	1		ENSP00000355802.4	P07099
EPHX1	ENST00000614058.4 link	c.852C>T	p.Pro284Pro	synonymous_variant	Exon 6 of 9	1		ENSP00000480004.1	P07099

Frequencies

GnomAD3 genomes

AF:

0.0459

AC:

6983

AN:

152154

Hom.:

222

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0272

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0493

Gnomad ASJ

AF:

0.0631

Gnomad EAS

AF:

0.145

Gnomad SAS

AF:

0.0907

Gnomad FIN

AF:

0.0814

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0399

Gnomad OTH

AF:

0.0503

GnomAD2 exomes

AF:

0.0605

AC:

15221

AN:

251488

AF XY:

0.0615

show subpopulations

Gnomad AFR exome

AF:

0.0251

Gnomad AMR exome

AF:

0.0567

Gnomad ASJ exome

AF:

0.0621

Gnomad EAS exome

AF:

0.151

Gnomad FIN exome

AF:

0.0814

Gnomad NFE exome

AF:

0.0409

Gnomad OTH exome

AF:

0.0507

GnomAD4 exome

AF:

0.0468

AC:

68383

AN:

1461868

Hom.:

2037

Cov.:

AF XY:

0.0483

AC XY:

35092

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.0238

AC:

797

AN:

33478

American (AMR)

AF:

0.0594

AC:

2657

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0595

AC:

1556

AN:

26134

East Asian (EAS)

AF:

0.147

AC:

5841

AN:

39700

South Asian (SAS)

AF:

0.0906

AC:

7819

AN:

86258

European-Finnish (FIN)

AF:

0.0779

AC:

4163

AN:

53420

Middle Eastern (MID)

AF:

0.0540

AC:

311

AN:

5764

European-Non Finnish (NFE)

AF:

0.0380

AC:

42214

AN:

1111996

Other (OTH)

AF:

0.0501

AC:

3025

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

4406

8812

13217

17623

22029

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1728

3456

5184

6912

8640

<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:

0.0460

AC:

7003

AN:

152272

Hom.:

227

Cov.:

AF XY:

0.0484

AC XY:

3606

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.0273

AC:

1135

AN:

41548

American (AMR)

AF:

0.0495

AC:

757

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0631

AC:

219

AN:

3470

East Asian (EAS)

AF:

0.145

AC:

750

AN:

5174

South Asian (SAS)

AF:

0.0910

AC:

439

AN:

4826

European-Finnish (FIN)

AF:

0.0814

AC:

864

AN:

10608

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0399

AC:

2716

AN:

68026

Other (OTH)

AF:

0.0560

AC:

118

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

346

693

1039

1386

1732

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

188

282

376

470

<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:

0.0427

Hom.:

605

Bravo

AF:

0.0423

Asia WGS

AF:

0.137

AC:

474

AN:

3478

EpiCase

AF:

0.0413

EpiControl

AF:

0.0403

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 09, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.68

CADD

Benign

9.6

(source)

DANN

Benign

0.75

PhyloP100

0.066

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over