1-225828866-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001136018.4(EPHX1):ā€‹c.137A>Gā€‹(p.Asp46Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000757 in 1,453,426 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 31)
Exomes š‘“: 0.0000076 ( 0 hom. )

Consequence

EPHX1
NM_001136018.4 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.75
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.12606645).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
EPHX1NM_001136018.4 linkuse as main transcriptc.137A>G p.Asp46Gly missense_variant 2/9 ENST00000272167.10 NP_001129490.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
EPHX1ENST00000272167.10 linkuse as main transcriptc.137A>G p.Asp46Gly missense_variant 2/91 NM_001136018.4 ENSP00000272167 P1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD3 exomes
AF:
0.00000852
AC:
2
AN:
234730
Hom.:
0
AF XY:
0.0000158
AC XY:
2
AN XY:
126708
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000193
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000757
AC:
11
AN:
1453426
Hom.:
0
Cov.:
32
AF XY:
0.00000692
AC XY:
5
AN XY:
722148
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000723
Gnomad4 OTH exome
AF:
0.0000333
GnomAD4 genome
Cov.:
31
Alfa
AF:
0.0000468
Hom.:
0
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsSep 12, 2023The c.137A>G (p.D46G) alteration is located in exon 2 (coding exon 1) of the EPHX1 gene. This alteration results from a A to G substitution at nucleotide position 137, causing the aspartic acid (D) at amino acid position 46 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.095
BayesDel_addAF
Benign
-0.24
T
BayesDel_noAF
Benign
-0.59
CADD
Benign
17
DANN
Uncertain
0.98
DEOGEN2
Benign
0.28
.;T;.;T;T
Eigen
Benign
-0.49
Eigen_PC
Benign
-0.36
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Benign
0.17
T;.;T;T;.
M_CAP
Benign
0.0088
T
MetaRNN
Benign
0.13
T;T;T;T;T
MetaSVM
Benign
-0.96
T
MutationAssessor
Benign
1.6
.;L;.;L;L
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.28
T
PROVEAN
Uncertain
-3.1
D;N;D;.;N
REVEL
Benign
0.068
Sift
Benign
0.18
T;T;T;.;T
Sift4G
Benign
0.30
T;T;T;T;T
Polyphen
0.025
.;B;.;B;B
Vest4
0.090, 0.091, 0.094
MutPred
0.15
Gain of methylation at R43 (P = 0.0641);Gain of methylation at R43 (P = 0.0641);Gain of methylation at R43 (P = 0.0641);Gain of methylation at R43 (P = 0.0641);Gain of methylation at R43 (P = 0.0641);
MVP
0.33
MPC
0.27
ClinPred
0.32
T
GERP RS
3.9
Varity_R
0.16
gMVP
0.41

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs779348131; hg19: chr1-226016567; COSMIC: COSV55299492; API