1-225818396-G-A

Variant names:

• chr1-225818396-G-A
• rs868966
• NM_001136018.4:c.-6+8227G>A

Variant summary

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

The NM_001136018.4(EPHX1):​c.-6+8227G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.552 in 152,006 control chromosomes in the GnomAD database, including 23,296 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 0.55 (23296 hom., cov: 31)
• Consequence: EPHX1 NM_001136018.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.48
• Publications: 13 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=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.585 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPHX1	NM_001136018.4	c.-6+8227G>A		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.-6+8227G>A		intron_variant	Intron 1 of 8	1	NM_001136018.4	ENSP00000272167.5
EPHX1	ENST00000614058.4	c.-6+7781G>A		intron_variant	Intron 1 of 8	1		ENSP00000480004.1
EPHX1	ENST00000448202.5	c.-6+7781G>A		intron_variant	Intron 1 of 3	2		ENSP00000408469.1

Frequencies

GnomAD3 genomes AF: 0.552 AC: 83859 AN: 151888 Hom.: 23282 Cov.: 31

Gnomad AFR AF: 0.591

Gnomad AMI AF: 0.515

Gnomad AMR AF: 0.553

Gnomad ASJ AF: 0.472

Gnomad EAS AF: 0.538

Gnomad SAS AF: 0.520

Gnomad FIN AF: 0.515

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.543

Gnomad OTH AF: 0.527

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

GnomAD4 genome AF: 0.552 AC: 83920 AN: 152006 Hom.: 23296 Cov.: 31 AF XY: 0.552 AC XY: 40986 AN XY: 74294

African (AFR) AF: 0.591 AC: 24509 AN: 41456

American (AMR) AF: 0.553 AC: 8446 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.472 AC: 1635 AN: 3466

East Asian (EAS) AF: 0.537 AC: 2776 AN: 5166

South Asian (SAS) AF: 0.520 AC: 2507 AN: 4822

European-Finnish (FIN) AF: 0.515 AC: 5435 AN: 10558

Middle Eastern (MID) AF: 0.432 AC: 126 AN: 292

European-Non Finnish (NFE) AF: 0.543 AC: 36918 AN: 67958

Other (OTH) AF: 0.521 AC: 1099 AN: 2110

Alfa AF: 0.548 Hom.: 54676

Bravo AF: 0.555

Asia WGS AF: 0.531 AC: 1846 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.12
DANN	Benign	0.56
PhyloP100		-1.5
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: rs868966; hg19: chr1-226006098;