Genetic Variant EPHX1:p.Lys416Asn (chr1-225845227-G-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001136018.4(EPHX1):c.1248G>T(p.Lys416Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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. K416R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

EPHX1
NM_001136018.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.44

Publications

10 publications found

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]

EPHX1 links:

ENSG00000242861 (HGNC:):

ENSG00000242861 links:

TMEM63A (HGNC:29118): (transmembrane protein 63A) Enables mechanosensitive ion channel activity. Predicted to be involved in cation transmembrane transport. Located in centriolar satellite and lysosomal membrane. Implicated in hypomyelinating leukodystrophy. [provided by Alliance of Genome Resources, Apr 2022]

TMEM63A Gene-Disease associations (from GenCC):

leukodystrophy, hypomyelinating, 19, transient infantile
Inheritance: AD Classification: STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

TMEM63A links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.894

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPHX1	NM_001136018.4 link	c.1248G>T	p.Lys416Asn	missense_variant	Exon 9 of 9	ENST00000272167.10	NP_001129490.1	P07099R4SBI6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EPHX1	ENST00000272167.10 link	c.1248G>T	p.Lys416Asn	missense_variant	Exon 9 of 9	1	NM_001136018.4	ENSP00000272167.5	P07099
EPHX1	ENST00000366837.5 link	c.1248G>T	p.Lys416Asn	missense_variant	Exon 9 of 9	1		ENSP00000355802.4	P07099
EPHX1	ENST00000614058.4 link	c.1248G>T	p.Lys416Asn	missense_variant	Exon 9 of 9	1		ENSP00000480004.1	P07099
ENSG00000242861	ENST00000424332.1 link	n.43+1253C>A		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

202

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.54

D;D;D

Eigen

Uncertain

0.22

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.74

.;T;.

M_CAP

Benign

0.030

MetaRNN

Pathogenic

0.89

D;D;D

MetaSVM

Benign

-0.81

MutationAssessor

Benign

1.9

L;L;L

PhyloP100

1.4

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-3.3

D;.;D

REVEL

Benign

0.12

Sift

Uncertain

0.016

D;.;D

Sift4G

Benign

0.068

T;T;T

Polyphen

0.88

P;P;P

Vest4

0.61

MutPred

0.59

Loss of methylation at K416 (P = 0.0111);Loss of methylation at K416 (P = 0.0111);Loss of methylation at K416 (P = 0.0111);

MVP

0.56

MPC

0.59

ClinPred

0.87

GERP RS

3.2

Varity_R

0.27

gMVP

0.75

Mutation Taster

=45/55

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over