rs3753661

Variant names:

• chr1-225826641-T-G
• rs3753661
• NM_001136018.4:c.-5-2084T>G

Variant summary

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

The NM_001136018.4(EPHX1):​c.-5-2084T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0803 in 151,966 control chromosomes in the GnomAD database, including 686 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 0.080 (686 hom., cov: 31)
• Consequence: EPHX1 NM_001136018.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.800
• Publications: 11 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.207 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPHX1	NM_001136018.4	MANE Select	c.-5-2084T>G		intron	N/A	NP_001129490.1
	EPHX1	NM_000120.4		c.-6+1097T>G		intron	N/A	NP_000111.1
	EPHX1	NM_001291163.2		c.-5-2084T>G		intron	N/A	NP_001278092.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPHX1	ENST00000272167.10	TSL:1 MANE Select	c.-5-2084T>G		intron	N/A	ENSP00000272167.5
	EPHX1	ENST00000366837.5	TSL:1	c.-6+1097T>G		intron	N/A	ENSP00000355802.4
	EPHX1	ENST00000614058.4	TSL:1	c.-5-2084T>G		intron	N/A	ENSP00000480004.1

Frequencies

GnomAD3 genomes AF: 0.0802 AC: 12171 AN: 151848 Hom.: 675 Cov.: 31

Gnomad AFR AF: 0.0176

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.130

Gnomad ASJ AF: 0.0979

Gnomad EAS AF: 0.217

Gnomad SAS AF: 0.170

Gnomad FIN AF: 0.0925

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.0855

Gnomad OTH AF: 0.101

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

GnomAD4 genome AF: 0.0803 AC: 12201 AN: 151966 Hom.: 686 Cov.: 31 AF XY: 0.0837 AC XY: 6220 AN XY: 74274

African (AFR) AF: 0.0176 AC: 729 AN: 41482

American (AMR) AF: 0.131 AC: 2006 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.0979 AC: 339 AN: 3464

East Asian (EAS) AF: 0.217 AC: 1115 AN: 5134

South Asian (SAS) AF: 0.171 AC: 822 AN: 4814

European-Finnish (FIN) AF: 0.0925 AC: 977 AN: 10566

Middle Eastern (MID) AF: 0.190 AC: 56 AN: 294

European-Non Finnish (NFE) AF: 0.0855 AC: 5807 AN: 67924

Other (OTH) AF: 0.106 AC: 224 AN: 2110

Alfa AF: 0.0877 Hom.: 2320

Bravo AF: 0.0816

Asia WGS AF: 0.184 AC: 640 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.52
DANN	Benign	0.45
PhyloP100		-0.80
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: rs3753661; hg19: chr1-226014342;