Genetic Variant EPHX1:p.Asn357Asn (chr1-225844528-C-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_001136018.4(EPHX1):c.1071C>T(p.Asn357Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.105 in 1,614,038 control chromosomes in the GnomAD database, including 10,119 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.099 ( 851 hom., cov: 32)

Exomes 𝑓: 0.11 ( 9268 hom. )

Consequence

EPHX1
NM_001136018.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.102

Publications

49 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.39).

BP6

Variant 1-225844528-C-T is Benign according to our data. Variant chr1-225844528-C-T is described in ClinVar as Benign. ClinVar VariationId is 1179465.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.102 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.222 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
EPHX1	NM_001136018.4	MANE Select	c.1071C>T	p.Asn357Asn	synonymous	Exon 8 of 9	NP_001129490.1
EPHX1	NM_000120.4		c.1071C>T	p.Asn357Asn	synonymous	Exon 8 of 9	NP_000111.1
EPHX1	NM_001291163.2		c.1071C>T	p.Asn357Asn	synonymous	Exon 8 of 9	NP_001278092.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
EPHX1	ENST00000272167.10	TSL:1 MANE Select	c.1071C>T	p.Asn357Asn	synonymous	Exon 8 of 9	ENSP00000272167.5
EPHX1	ENST00000366837.5	TSL:1	c.1071C>T	p.Asn357Asn	synonymous	Exon 8 of 9	ENSP00000355802.4
EPHX1	ENST00000614058.4	TSL:1	c.1071C>T	p.Asn357Asn	synonymous	Exon 8 of 9	ENSP00000480004.1

Frequencies

GnomAD3 genomes

AF:

0.0989

AC:

15037

AN:

152062

Hom.:

850

Cov.:

show subpopulations

Gnomad AFR

AF:

0.106

Gnomad AMI

AF:

0.0560

Gnomad AMR

AF:

0.0690

Gnomad ASJ

AF:

0.0810

Gnomad EAS

AF:

0.130

Gnomad SAS

AF:

0.233

Gnomad FIN

AF:

0.0567

Gnomad MID

AF:

0.108

Gnomad NFE

AF:

0.0975

Gnomad OTH

AF:

0.103

GnomAD2 exomes

AF:

0.106

AC:

26723

AN:

251446

AF XY:

0.114

show subpopulations

Gnomad AFR exome

AF:

0.110

Gnomad AMR exome

AF:

0.0439

Gnomad ASJ exome

AF:

0.0678

Gnomad EAS exome

AF:

0.126

Gnomad FIN exome

AF:

0.0541

Gnomad NFE exome

AF:

0.103

Gnomad OTH exome

AF:

0.0954

GnomAD4 exome

AF:

0.106

AC:

155071

AN:

1461858

Hom.:

9268

Cov.:

AF XY:

0.110

AC XY:

79966

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.109

AC:

3658

AN:

33476

American (AMR)

AF:

0.0457

AC:

2043

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0737

AC:

1925

AN:

26134

East Asian (EAS)

AF:

0.141

AC:

5578

AN:

39698

South Asian (SAS)

AF:

0.224

AC:

19282

AN:

86256

European-Finnish (FIN)

AF:

0.0590

AC:

3150

AN:

53418

Middle Eastern (MID)

AF:

0.0985

AC:

568

AN:

5768

European-Non Finnish (NFE)

AF:

0.101

AC:

112611

AN:

1111994

Other (OTH)

AF:

0.104

AC:

6256

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

8895

17790

26686

35581

44476

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4164

8328

12492

16656

20820

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0989

AC:

15047

AN:

152180

Hom.:

851

Cov.:

AF XY:

0.0975

AC XY:

7254

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.105

AC:

4381

AN:

41526

American (AMR)

AF:

0.0689

AC:

1054

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0810

AC:

281

AN:

3470

East Asian (EAS)

AF:

0.130

AC:

672

AN:

5168

South Asian (SAS)

AF:

0.233

AC:

1122

AN:

4816

European-Finnish (FIN)

AF:

0.0567

AC:

601

AN:

10602

Middle Eastern (MID)

AF:

0.102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0976

AC:

6632

AN:

67980

Other (OTH)

AF:

0.106

AC:

223

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

697

1394

2091

2788

3485

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

184

368

552

736

920

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0984

Hom.:

3316

Bravo

AF:

0.0956

Asia WGS

AF:

0.161

AC:

558

AN:

3478

EpiCase

AF:

0.0959

EpiControl

AF:

0.0960

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Nov 11, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Benign

0.85

PhyloP100

0.10

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over