NM_001136018.4:c.-5-3849T>C

Variant names:

• chr1-225824876-T-C
• rs2854450
• NM_001136018.4:c.-5-3849T>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.-5-3849T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.728 in 152,118 control chromosomes in the GnomAD database, including 41,841 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 0.73 (41841 hom., cov: 32)
• Consequence: EPHX1 NM_001136018.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.117
• Publications: 15 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=-0.93).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.921 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.-5-3849T>C		intron	N/A	NP_001129490.1
	EPHX1	NM_001291163.2		c.-5-3849T>C		intron	N/A	NP_001278092.1
	EPHX1	NM_001378426.1		c.-5-3849T>C		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.-5-3849T>C		intron	N/A	ENSP00000272167.5
	EPHX1	ENST00000614058.4	TSL:1	c.-5-3849T>C		intron	N/A	ENSP00000480004.1
	EPHX1	ENST00000448202.5	TSL:2	c.-5-3849T>C		intron	N/A	ENSP00000408469.1

Frequencies

GnomAD3 genomes AF: 0.728 AC: 110673 AN: 152000 Hom.: 41824 Cov.: 32

Gnomad AFR AF: 0.508

Gnomad AMI AF: 0.886

Gnomad AMR AF: 0.782

Gnomad ASJ AF: 0.772

Gnomad EAS AF: 0.939

Gnomad SAS AF: 0.944

Gnomad FIN AF: 0.811

Gnomad MID AF: 0.761

Gnomad NFE AF: 0.800

Gnomad OTH AF: 0.742

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

GnomAD4 genome AF: 0.728 AC: 110728 AN: 152118 Hom.: 41841 Cov.: 32 AF XY: 0.735 AC XY: 54673 AN XY: 74362

African (AFR) AF: 0.508 AC: 21039 AN: 41440

American (AMR) AF: 0.782 AC: 11959 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.772 AC: 2679 AN: 3470

East Asian (EAS) AF: 0.939 AC: 4870 AN: 5186

South Asian (SAS) AF: 0.944 AC: 4541 AN: 4812

European-Finnish (FIN) AF: 0.811 AC: 8608 AN: 10610

Middle Eastern (MID) AF: 0.753 AC: 220 AN: 292

European-Non Finnish (NFE) AF: 0.801 AC: 54429 AN: 67992

Other (OTH) AF: 0.745 AC: 1575 AN: 2114

Alfa AF: 0.759 Hom.: 18441

Bravo AF: 0.712

Asia WGS AF: 0.920 AC: 3199 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	3.4
DANN	Benign	0.47
PhyloP100		-0.12
PromoterAI		0.016	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: rs2854450; hg19: chr1-226012577; COSMIC: COSV55299730; COSMIC: COSV55299730;