1-225828874-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

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 (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0058 (10 hom., cov: 31)
  • Exomes 𝑓: 0.00056 (8 hom.)
• Consequence: EPHX1 NM_001136018.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.763

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=0.0116193).
• BP6: Variant 1-225828874-C-T is Benign according to our data. Variant chr1-225828874-C-T is described in ClinVar as [Benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPHX1	NM_001136018.4	c.145C>T	p.Arg49Cys	missense_variant	2/9	ENST00000272167.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPHX1	ENST00000272167.10	c.145C>T	p.Arg49Cys	missense_variant	2/9	1	NM_001136018.4	P1

Frequencies

GnomAD3 genomes AF: 0.00580 AC: 877 AN: 151246 Hom.: 10 Cov.: 31

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

GnomAD3 exomes AF: 0.00144 AC: 326 AN: 226284 Hom.: 3 AF XY: 0.00107 AC XY: 130 AN XY: 122046

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 SAS exome AF: 0.000105

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.: 8 Cov.: 32 AF XY: 0.000495 AC XY: 356 AN XY: 719386

Gnomad4 AFR exome AF: 0.0193

Gnomad4 AMR exome AF: 0.00155

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000506

Gnomad4 SAS exome AF: 0.0000354

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000254

Gnomad4 OTH exome AF: 0.00119

GnomAD4 genome AF: 0.00582 AC: 881 AN: 151370 Hom.: 10 Cov.: 31 AF XY: 0.00552 AC XY: 408 AN XY: 73936

Gnomad4 AFR AF: 0.0204

Gnomad4 AMR AF: 0.00211

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000442

Gnomad4 OTH AF: 0.00334

Alfa AF: 0.000941 Hom.: 3

Bravo AF: 0.00662

ESP6500AA AF: 0.0177 AC: 78

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00160 AC: 194

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 06, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.34
Cadd	Uncertain	24
Dann	Pathogenic	1.0
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D;.;D;D;.
MetaRNN	Benign	0.012	T;T;T;T;T
MetaSVM	Benign	-0.53	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.22	T
PROVEAN	Pathogenic	-5.4	D;D;D;.;D
REVEL	Benign	0.22
Sift	Uncertain	0.0050	D;D;D;.;D
Sift4G	Uncertain	0.0020	D;D;D;D;D
Polyphen		0.99	.;D;.;D;D
Vest4		0.20, 0.20
MVP		0.50
MPC		0.29
ClinPred		0.051	T
GERP RS		5.0
Varity_R		0.37
gMVP		0.67

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: rs2234697; hg19: chr1-226016575;