1-225824985-G-T

Variant names:

• chr1-225824985-G-T
• rs3753658
• NM_001136018.4:c.-5-3740G>T

Variant summary

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

The NM_001136018.4(EPHX1):​c.-5-3740G>T 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 152,220 control chromosomes in the GnomAD database, including 1,081 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 (1081 hom., cov: 33)
• Consequence: EPHX1 NM_001136018.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.584
• Publications: 19 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=-0.77).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.185 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.-5-3740G>T		intron	N/A	NP_001129490.1
	EPHX1	NM_001291163.2		c.-5-3740G>T		intron	N/A	NP_001278092.1
	EPHX1	NM_001378426.1		c.-5-3740G>T		intron	N/A	NP_001365355.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPHX1	ENST00000272167.10	TSL:1 MANE Select	c.-5-3740G>T		intron	N/A	ENSP00000272167.5
	EPHX1	ENST00000614058.4	TSL:1	c.-5-3740G>T		intron	N/A	ENSP00000480004.1
	EPHX1	ENST00000448202.5	TSL:2	c.-5-3740G>T		intron	N/A	ENSP00000408469.1

Frequencies

GnomAD3 genomes AF: 0.105 AC: 15971 AN: 152102 Hom.: 1083 Cov.: 33

Gnomad AFR AF: 0.0246

Gnomad AMI AF: 0.221

Gnomad AMR AF: 0.111

Gnomad ASJ AF: 0.122

Gnomad EAS AF: 0.195

Gnomad SAS AF: 0.184

Gnomad FIN AF: 0.154

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: 15963 AN: 152220 Hom.: 1081 Cov.: 33 AF XY: 0.108 AC XY: 8057 AN XY: 74424

African (AFR) AF: 0.0246 AC: 1020 AN: 41536

American (AMR) AF: 0.111 AC: 1692 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.122 AC: 424 AN: 3470

East Asian (EAS) AF: 0.195 AC: 1005 AN: 5164

South Asian (SAS) AF: 0.185 AC: 892 AN: 4822

European-Finnish (FIN) AF: 0.154 AC: 1635 AN: 10596

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

European-Non Finnish (NFE) AF: 0.130 AC: 8852 AN: 68006

Other (OTH) AF: 0.103 AC: 217 AN: 2116

Alfa AF: 0.118 Hom.: 3534

Bravo AF: 0.0977

Asia WGS AF: 0.169 AC: 589 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	5.8
DANN	Benign	0.83
PhyloP100		-0.58
PromoterAI		0.0077	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: rs3753658; hg19: chr1-226012686; COSMIC: COSV55299741; COSMIC: COSV55299741;