1-225831952-G-A

Variant names:

• chr1-225831952-G-A
• rs1131873
• NM_001136018.4:c.357G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001136018.4(EPHX1):​c.357G>A​(p.Lys119Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.15 in 1,613,702 control chromosomes in the GnomAD database, including 19,504 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1712 hom., cov: 33)
  • Exomes 𝑓: 0.15 (17792 hom.)
• Consequence: EPHX1 NM_001136018.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.38
• Publications: 39 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26).
• BP6: Variant 1-225831952-G-A is Benign according to our data. Variant chr1-225831952-G-A is described in ClinVar as Benign. ClinVar VariationId is 1286409.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.38 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.3 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.357G>A	p.Lys119Lys	synonymous	Exon 3 of 9	NP_001129490.1
	EPHX1	NM_000120.4		c.357G>A	p.Lys119Lys	synonymous	Exon 3 of 9	NP_000111.1
	EPHX1	NM_001291163.2		c.357G>A	p.Lys119Lys	synonymous	Exon 3 of 9	NP_001278092.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPHX1	ENST00000272167.10	TSL:1 MANE Select	c.357G>A	p.Lys119Lys	synonymous	Exon 3 of 9	ENSP00000272167.5
	EPHX1	ENST00000366837.5	TSL:1	c.357G>A	p.Lys119Lys	synonymous	Exon 3 of 9	ENSP00000355802.4
	EPHX1	ENST00000614058.4	TSL:1	c.357G>A	p.Lys119Lys	synonymous	Exon 3 of 9	ENSP00000480004.1

Frequencies

GnomAD3 genomes AF: 0.143 AC: 21791 AN: 152054 Hom.: 1704 Cov.: 33

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.216

Gnomad AMR AF: 0.127

Gnomad ASJ AF: 0.201

Gnomad EAS AF: 0.313

Gnomad SAS AF: 0.221

Gnomad FIN AF: 0.112

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.138

Gnomad OTH AF: 0.148

GnomAD2 exomes AF: 0.158 AC: 39728 AN: 251312 AF XY: 0.162

Gnomad AFR exome AF: 0.129

Gnomad AMR exome AF: 0.109

Gnomad ASJ exome AF: 0.192

Gnomad EAS exome AF: 0.306

Gnomad FIN exome AF: 0.113

Gnomad NFE exome AF: 0.141

Gnomad OTH exome AF: 0.143

GnomAD4 exome AF: 0.151 AC: 220586 AN: 1461530 Hom.: 17792 Cov.: 36 AF XY: 0.153 AC XY: 111289 AN XY: 727086

African (AFR) AF: 0.132 AC: 4404 AN: 33470

American (AMR) AF: 0.113 AC: 5034 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.191 AC: 4981 AN: 26136

East Asian (EAS) AF: 0.311 AC: 12329 AN: 39698

South Asian (SAS) AF: 0.225 AC: 19419 AN: 86252

European-Finnish (FIN) AF: 0.116 AC: 6183 AN: 53296

Middle Eastern (MID) AF: 0.126 AC: 724 AN: 5768

European-Non Finnish (NFE) AF: 0.143 AC: 158470 AN: 1111802

Other (OTH) AF: 0.150 AC: 9042 AN: 60390

GnomAD4 genome AF: 0.143 AC: 21804 AN: 152172 Hom.: 1712 Cov.: 33 AF XY: 0.144 AC XY: 10703 AN XY: 74364

African (AFR) AF: 0.128 AC: 5320 AN: 41518

American (AMR) AF: 0.127 AC: 1938 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.201 AC: 698 AN: 3472

East Asian (EAS) AF: 0.313 AC: 1621 AN: 5178

South Asian (SAS) AF: 0.222 AC: 1069 AN: 4816

European-Finnish (FIN) AF: 0.112 AC: 1186 AN: 10574

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.138 AC: 9414 AN: 68016

Other (OTH) AF: 0.155 AC: 328 AN: 2112

Alfa AF: 0.144 Hom.: 4831

Bravo AF: 0.143

Asia WGS AF: 0.267 AC: 926 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Benign	6.1
DANN	Benign	0.67
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: rs1131873; hg19: chr1-226019653; COSMIC: COSV55300861;