NM_001136018.4:c.-5-1127A>G

Variant names:

• chr1-225827598-A-G
• rs3738043
• NM_001136018.4:c.-5-1127A>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.-5-1127A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.097 in 152,222 control chromosomes in the GnomAD database, including 851 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 0.097 (851 hom., cov: 33)
• Consequence: EPHX1 NM_001136018.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.44
• 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=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.2 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPHX1	NM_001136018.4	c.-5-1127A>G		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.-5-1127A>G		intron_variant	Intron 1 of 8	1	NM_001136018.4	ENSP00000272167.5
EPHX1	ENST00000366837.5	c.-5-1127A>G		intron_variant	Intron 1 of 8	1		ENSP00000355802.4
EPHX1	ENST00000614058.4	c.-5-1127A>G		intron_variant	Intron 1 of 8	1		ENSP00000480004.1
EPHX1	ENST00000448202.5	c.-5-1127A>G		intron_variant	Intron 1 of 3	2		ENSP00000408469.1

Frequencies

GnomAD3 genomes AF: 0.0968 AC: 14725 AN: 152104 Hom.: 840 Cov.: 33

Gnomad AFR AF: 0.0735

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.141

Gnomad ASJ AF: 0.100

Gnomad EAS AF: 0.210

Gnomad SAS AF: 0.169

Gnomad FIN AF: 0.0919

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.0860

Gnomad OTH AF: 0.120

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

GnomAD4 genome AF: 0.0970 AC: 14763 AN: 152222 Hom.: 851 Cov.: 33 AF XY: 0.100 AC XY: 7445 AN XY: 74442

African (AFR) AF: 0.0735 AC: 3053 AN: 41552

American (AMR) AF: 0.143 AC: 2181 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.100 AC: 348 AN: 3472

East Asian (EAS) AF: 0.211 AC: 1088 AN: 5168

South Asian (SAS) AF: 0.170 AC: 819 AN: 4822

European-Finnish (FIN) AF: 0.0919 AC: 975 AN: 10606

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.0860 AC: 5849 AN: 67990

Other (OTH) AF: 0.125 AC: 263 AN: 2108

Alfa AF: 0.0950 Hom.: 1492

Bravo AF: 0.101

Asia WGS AF: 0.188 AC: 654 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.13
DANN	Benign	0.34
PhyloP100		-1.4
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: rs3738043; hg19: chr1-226015299;