rs3753660

Variant names:

• chr1-225825075-T-C
• rs3753660
• NM_001136018.4:c.-5-3650T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001136018.4(EPHX1):​c.-5-3650T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.105 in 152,268 control chromosomes in the GnomAD database, including 1,085 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.10 (1085 hom., cov: 32)
• Consequence: EPHX1 NM_001136018.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.29
• Publications: 6 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.185 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPHX1	NM_001136018.4	c.-5-3650T>C		intron_variant	Intron 1 of 8	ENST00000272167.10	NP_001129490.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPHX1	ENST00000272167.10	c.-5-3650T>C		intron_variant	Intron 1 of 8	1	NM_001136018.4	ENSP00000272167.5
EPHX1	ENST00000614058.4	c.-5-3650T>C		intron_variant	Intron 1 of 8	1		ENSP00000480004.1
EPHX1	ENST00000448202.5	c.-5-3650T>C		intron_variant	Intron 1 of 3	2		ENSP00000408469.1

Frequencies

GnomAD3 genomes AF: 0.105 AC: 15975 AN: 152152 Hom.: 1087 Cov.: 32

Gnomad AFR AF: 0.0246

Gnomad AMI AF: 0.220

Gnomad AMR AF: 0.111

Gnomad ASJ AF: 0.122

Gnomad EAS AF: 0.195

Gnomad SAS AF: 0.184

Gnomad FIN AF: 0.155

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.130

Gnomad OTH AF: 0.102

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.105 AC: 15968 AN: 152268 Hom.: 1085 Cov.: 32 AF XY: 0.108 AC XY: 8059 AN XY: 74450

African (AFR) AF: 0.0245 AC: 1018 AN: 41560

American (AMR) AF: 0.111 AC: 1691 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.122 AC: 424 AN: 3472

East Asian (EAS) AF: 0.195 AC: 1008 AN: 5178

South Asian (SAS) AF: 0.184 AC: 890 AN: 4824

European-Finnish (FIN) AF: 0.155 AC: 1642 AN: 10604

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.130 AC: 8850 AN: 68016

Other (OTH) AF: 0.104 AC: 219 AN: 2108

Alfa AF: 0.121 Hom.: 834

Bravo AF: 0.0977

Asia WGS AF: 0.169 AC: 588 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	7.1
DANN	Benign	0.60
PhyloP100		1.3
PromoterAI		-0.013	Neutral
Mutation Taster		=100/0	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: rs3753660; hg19: chr1-226012776; COSMIC: COSV55299763; COSMIC: COSV55299763;