rs1051740

Positions:

• chr1-225831932-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001136018.4(EPHX1):​c.337T>C​(p.Tyr113His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.303 in 1,613,706 control chromosomes in the GnomAD database, including 76,258 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6305 hom., cov: 32)
  • Exomes 𝑓: 0.31 (69953 hom.)
• Consequence: EPHX1 NM_001136018.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: 7.79

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0057053864).
• BP6: Variant 1-225831932-T-C is Benign according to our data. Variant chr1-225831932-T-C is described in ClinVar as [Benign]. Clinvar id is 16604.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.434 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPHX1	NM_001136018.4	c.337T>C	p.Tyr113His	missense_variant	3/9	ENST00000272167.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPHX1	ENST00000272167.10	c.337T>C	p.Tyr113His	missense_variant	3/9	1	NM_001136018.4	P1

Frequencies

GnomAD3 genomes AF: 0.278 AC: 42243 AN: 151976 Hom.: 6297 Cov.: 32

Gnomad AFR AF: 0.184

Gnomad AMI AF: 0.296

Gnomad AMR AF: 0.328

Gnomad ASJ AF: 0.288

Gnomad EAS AF: 0.449

Gnomad SAS AF: 0.368

Gnomad FIN AF: 0.297

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.301

Gnomad OTH AF: 0.278

GnomAD3 exomes AF: 0.321 AC: 80762 AN: 251384 Hom.: 13625 AF XY: 0.321 AC XY: 43628 AN XY: 135882

Gnomad AFR exome AF: 0.178

Gnomad AMR exome AF: 0.393

Gnomad ASJ exome AF: 0.283

Gnomad EAS exome AF: 0.461

Gnomad SAS exome AF: 0.352

Gnomad FIN exome AF: 0.301

Gnomad NFE exome AF: 0.297

Gnomad OTH exome AF: 0.307

GnomAD4 exome AF: 0.306 AC: 447402 AN: 1461612 Hom.: 69953 Cov.: 44 AF XY: 0.307 AC XY: 223561 AN XY: 727134

Gnomad4 AFR exome AF: 0.181

Gnomad4 AMR exome AF: 0.382

Gnomad4 ASJ exome AF: 0.291

Gnomad4 EAS exome AF: 0.440

Gnomad4 SAS exome AF: 0.351

Gnomad4 FIN exome AF: 0.298

Gnomad4 NFE exome AF: 0.299

Gnomad4 OTH exome AF: 0.308

GnomAD4 genome AF: 0.278 AC: 42272 AN: 152094 Hom.: 6305 Cov.: 32 AF XY: 0.280 AC XY: 20809 AN XY: 74322

Gnomad4 AFR AF: 0.185

Gnomad4 AMR AF: 0.328

Gnomad4 ASJ AF: 0.288

Gnomad4 EAS AF: 0.449

Gnomad4 SAS AF: 0.366

Gnomad4 FIN AF: 0.297

Gnomad4 NFE AF: 0.301

Gnomad4 OTH AF: 0.276

Alfa AF: 0.295 Hom.: 12549

Bravo AF: 0.276

TwinsUK AF: 0.293 AC: 1086

ALSPAC AF: 0.315 AC: 1215

ESP6500AA AF: 0.176 AC: 776

ESP6500EA AF: 0.300 AC: 2577

ExAC AF: 0.313 AC: 38044

Asia WGS AF: 0.394 AC: 1370 AN: 3478

EpiCase AF: 0.302

EpiControl AF: 0.294

ClinVar

Significance: Benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	This variant is associated with the following publications: (PMID: 23580125, 7516776, 15061915, 15355699, 22206016, 23451147, 21445251, 19952982, 8944076, 20932192, 15535985, 22610071, 19307236, 21649467, 18439551, 25087612) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

EPOXIDE HYDROLASE 1 POLYMORPHISM Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Jun 01, 2001

- -

Cystic fibrosis Other:1

risk factor, no assertion criteria provided

research

Center for Computational Genomics and Data Science, University of Alabama

Apr 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	.;T;.;T;T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D;.;D;D;.
MetaRNN	Benign	0.0057	T;T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.9	.;L;.;L;L
MutationTaster	Benign	9.7e-7	P;P
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-4.3	D;D;D;.;D
REVEL	Uncertain	0.46
Sift	Uncertain	0.012	D;D;D;.;D
Sift4G	Pathogenic	0.0	D;D;T;D;D
Polyphen		1.0	.;D;.;D;D
Vest4		0.20, 0.38, 0.22
MPC		0.86
ClinPred		0.0077	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.75
gMVP		0.85

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: rs1051740; hg19: chr1-226019633; COSMIC: COSV55298811;