1-225831799-T-C

Variant names:

• chr1-225831799-T-C
• rs2234698
• NM_001136018.4:c.204T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001136018.4(EPHX1):​c.204T>C​(p.Asp68Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0181 in 1,614,094 control chromosomes in the GnomAD database, including 321 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.012 (18 hom., cov: 32)
  • Exomes 𝑓: 0.019 (303 hom.)
• Consequence: EPHX1 NM_001136018.4 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -1.19
• Publications: 14 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=-0.83).
• BP6: Variant 1-225831799-T-C is Benign according to our data. Variant chr1-225831799-T-C is described in ClinVar as Benign. ClinVar VariationId is 3037613.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-1.19 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0119 (1819/152266) while in subpopulation NFE AF = 0.0199 (1355/68022). AF 95% confidence interval is 0.019. There are 18 homozygotes in GnomAd4. There are 791 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 18 AR,AD gene

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.204T>C	p.Asp68Asp	synonymous	Exon 3 of 9	NP_001129490.1	R4SBI6
	EPHX1	NM_000120.4		c.204T>C	p.Asp68Asp	synonymous	Exon 3 of 9	NP_000111.1	R4SBI6
	EPHX1	NM_001291163.2		c.204T>C	p.Asp68Asp	synonymous	Exon 3 of 9	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.204T>C	p.Asp68Asp	synonymous	Exon 3 of 9	ENSP00000272167.5	P07099
	EPHX1	ENST00000366837.5	TSL:1	c.204T>C	p.Asp68Asp	synonymous	Exon 3 of 9	ENSP00000355802.4	P07099
	EPHX1	ENST00000614058.4	TSL:1	c.204T>C	p.Asp68Asp	synonymous	Exon 3 of 9	ENSP00000480004.1	P07099

Frequencies

GnomAD3 genomes AF: 0.0119 AC: 1818 AN: 152148 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.00369

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.00923

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00725

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0199

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.0116 AC: 2911 AN: 251488 AF XY: 0.0117

Gnomad AFR exome AF: 0.00283

Gnomad AMR exome AF: 0.00558

Gnomad ASJ exome AF: 0.00228

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00725

Gnomad NFE exome AF: 0.0202

Gnomad OTH exome AF: 0.0134

GnomAD4 exome AF: 0.0187 AC: 27329 AN: 1461828 Hom.: 303 Cov.: 32 AF XY: 0.0181 AC XY: 13175 AN XY: 727222

African (AFR) AF: 0.00257 AC: 86 AN: 33480

American (AMR) AF: 0.00595 AC: 266 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00203 AC: 53 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00370 AC: 319 AN: 86250

European-Finnish (FIN) AF: 0.00758 AC: 405 AN: 53418

Middle Eastern (MID) AF: 0.00296 AC: 17 AN: 5748

European-Non Finnish (NFE) AF: 0.0228 AC: 25399 AN: 1111982

Other (OTH) AF: 0.0130 AC: 784 AN: 60392

GnomAD4 genome AF: 0.0119 AC: 1819 AN: 152266 Hom.: 18 Cov.: 32 AF XY: 0.0106 AC XY: 791 AN XY: 74452

African (AFR) AF: 0.00368 AC: 153 AN: 41558

American (AMR) AF: 0.00922 AC: 141 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3468

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5172

South Asian (SAS) AF: 0.00373 AC: 18 AN: 4824

European-Finnish (FIN) AF: 0.00725 AC: 77 AN: 10616

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0199 AC: 1355 AN: 68022

Other (OTH) AF: 0.0119 AC: 25 AN: 2106

Alfa AF: 0.0174 Hom.: 151

Bravo AF: 0.0120

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0183

EpiControl AF: 0.0188

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	EPHX1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.3
DANN	Benign	0.45
PhyloP100		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2234698; hg19: chr1-226019500;