1-225828874-C-A

Variant names:

• chr1-225828874-C-A
• rs2234697
• NM_001136018.4:c.145C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001136018.4(EPHX1):​c.145C>A​(p.Arg49Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,448,738 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R49C) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: EPHX1 NM_001136018.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.763
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.145C>A	p.Arg49Ser	missense	Exon 2 of 9	NP_001129490.1	R4SBI6
	EPHX1	NM_000120.4		c.145C>A	p.Arg49Ser	missense	Exon 2 of 9	NP_000111.1	R4SBI6
	EPHX1	NM_001291163.2		c.145C>A	p.Arg49Ser	missense	Exon 2 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.145C>A	p.Arg49Ser	missense	Exon 2 of 9	ENSP00000272167.5	P07099
	EPHX1	ENST00000366837.5	TSL:1	c.145C>A	p.Arg49Ser	missense	Exon 2 of 9	ENSP00000355802.4	P07099
	EPHX1	ENST00000614058.4	TSL:1	c.145C>A	p.Arg49Ser	missense	Exon 2 of 9	ENSP00000480004.1	P07099

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1448738 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 719386

African (AFR) AF: 0.00 AC: 0 AN: 33278

American (AMR) AF: 0.00 AC: 0 AN: 43318

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25768

East Asian (EAS) AF: 0.00 AC: 0 AN: 39508

South Asian (SAS) AF: 0.00 AC: 0 AN: 84712

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5674

European-Non Finnish (NFE) AF: 0.00000272 AC: 3 AN: 1104102

Other (OTH) AF: 0.00 AC: 0 AN: 59804

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.45	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.76
PrimateAI	Benign	0.22	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.19
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.010	D
Polyphen		0.54	P
Vest4		0.38
MutPred		0.58		Gain of glycosylation at R49 (P = 0.0174)
MVP		0.48
MPC		0.32
ClinPred		0.97	D
GERP RS		5.0
Varity_R		0.51
gMVP		0.62
Mutation Taster		=82/18	polymorphism

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: rs2234697; hg19: chr1-226016575;