rs3817268

Variant names:

• chr1-225831670-G-T
• rs3817268
• NM_001136018.4:c.184-109G>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001136018.4(EPHX1):​c.184-109G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.243 in 1,059,036 control chromosomes in the GnomAD database, including 32,014 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.25 (4799 hom., cov: 32)
  • Exomes 𝑓: 0.24 (27215 hom.)
• Consequence: EPHX1 NM_001136018.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.39
• Publications: 3 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: Unknown Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 1-225831670-G-T is Benign according to our data. Variant chr1-225831670-G-T is described in ClinVar as Benign. ClinVar VariationId is 1259870.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.248 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPHX1	NM_001136018.4	MANE Select	c.184-109G>T		intron	N/A	NP_001129490.1	R4SBI6
	EPHX1	NM_000120.4		c.184-109G>T		intron	N/A	NP_000111.1	R4SBI6
	EPHX1	NM_001291163.2		c.184-109G>T		intron	N/A	NP_001278092.1	P07099

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPHX1	ENST00000272167.10	TSL:1 MANE Select	c.184-109G>T		intron	N/A	ENSP00000272167.5	P07099
	EPHX1	ENST00000366837.5	TSL:1	c.184-109G>T		intron	N/A	ENSP00000355802.4	P07099
	EPHX1	ENST00000614058.4	TSL:1	c.184-109G>T		intron	N/A	ENSP00000480004.1	P07099

Frequencies

GnomAD3 genomes AF: 0.250 AC: 38009 AN: 151962 Hom.: 4795 Cov.: 32

Gnomad AFR AF: 0.243

Gnomad AMI AF: 0.285

Gnomad AMR AF: 0.254

Gnomad ASJ AF: 0.221

Gnomad EAS AF: 0.203

Gnomad SAS AF: 0.195

Gnomad FIN AF: 0.322

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.251

Gnomad OTH AF: 0.250

GnomAD4 exome AF: 0.242 AC: 219242 AN: 906956 Hom.: 27215 AF XY: 0.241 AC XY: 113725 AN XY: 470964

African (AFR) AF: 0.244 AC: 5486 AN: 22460

American (AMR) AF: 0.256 AC: 9860 AN: 38556

Ashkenazi Jewish (ASJ) AF: 0.219 AC: 4901 AN: 22372

East Asian (EAS) AF: 0.214 AC: 7623 AN: 35680

South Asian (SAS) AF: 0.196 AC: 14102 AN: 72062

European-Finnish (FIN) AF: 0.328 AC: 15461 AN: 47086

Middle Eastern (MID) AF: 0.264 AC: 824 AN: 3124

European-Non Finnish (NFE) AF: 0.242 AC: 150970 AN: 623464

Other (OTH) AF: 0.238 AC: 10015 AN: 42152

GnomAD4 genome AF: 0.250 AC: 38035 AN: 152080 Hom.: 4799 Cov.: 32 AF XY: 0.251 AC XY: 18670 AN XY: 74332

African (AFR) AF: 0.243 AC: 10079 AN: 41492

American (AMR) AF: 0.254 AC: 3883 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.221 AC: 765 AN: 3466

East Asian (EAS) AF: 0.203 AC: 1053 AN: 5178

South Asian (SAS) AF: 0.194 AC: 936 AN: 4824

European-Finnish (FIN) AF: 0.322 AC: 3399 AN: 10548

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.251 AC: 17073 AN: 67978

Other (OTH) AF: 0.249 AC: 524 AN: 2108

Alfa AF: 0.252 Hom.: 8867

Bravo AF: 0.246

Asia WGS AF: 0.198 AC: 692 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.059
DANN	Benign	0.61
PhyloP100		-2.4
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: rs3817268; hg19: chr1-226019371; COSMIC: COSV55301741;