Genetic Variant NM_001136018.4:c.*35A>T (chr1-225845382-A-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001136018.4(EPHX1):c.*35A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000691 in 1,302,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 0)

Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

EPHX1
NM_001136018.4 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.439

Publications

12 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: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPHX1	NM_001136018.4 link	c.*35A>T		3_prime_UTR_variant	Exon 9 of 9	ENST00000272167.10	NP_001129490.1	P07099R4SBI6
TMEM63A	NM_014698.3 link	c.*1557T>A		downstream_gene_variant		ENST00000366835.8	NP_055513.2	O94886A1NY77

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPHX1	ENST00000272167.10 link	c.*35A>T		3_prime_UTR_variant	Exon 9 of 9	1	NM_001136018.4	ENSP00000272167.5		P07099
TMEM63A	ENST00000366835.8 link	c.*1557T>A		downstream_gene_variant		1	NM_014698.3	ENSP00000355800.3		O94886

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000673

AC:

AN:

148610

AF XY:

0.0000123

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000120

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000691

AC:

AN:

1302004

Hom.:

Cov.:

AF XY:

0.00000467

AC XY:

AN XY:

642228

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29310

American (AMR)

AF:

0.00

AC:

AN:

34302

Ashkenazi Jewish (ASJ)

AF:

0.0000459

AC:

AN:

21802

East Asian (EAS)

AF:

0.00

AC:

AN:

29650

South Asian (SAS)

AF:

0.00

AC:

AN:

78762

European-Finnish (FIN)

AF:

0.0000906

AC:

AN:

33106

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3594

European-Non Finnish (NFE)

AF:

0.00000491

AC:

AN:

1019358

Other (OTH)

AF:

0.00

AC:

AN:

52120

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.536

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

2.2

(source)

DANN

Benign

0.81

PhyloP100

-0.44

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over