1-225845382-A-C

Variant names:

• chr1-225845382-A-C
• rs4653695
• NM_001136018.4:c.*35A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001136018.4(EPHX1):​c.*35A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.119 in 1,352,544 control chromosomes in the GnomAD database, including 9,841 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (934 hom., cov: 0)
  • Exomes 𝑓: 0.11 (8907 hom.)
• Consequence: EPHX1 NM_001136018.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.439
• Publications: 12 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]

ENSG00000242861 (HGNC:):

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)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 1-225845382-A-C is Benign according to our data. Variant chr1-225845382-A-C is described in ClinVar as Benign. ClinVar VariationId is 1248948.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.387 is higher than 0.05.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.275 AC: 14003 AN: 50984 Hom.: 932 Cov.: 0

Gnomad AFR AF: 0.115

Gnomad AMI AF: 0.411

Gnomad AMR AF: 0.399

Gnomad ASJ AF: 0.184

Gnomad EAS AF: 0.256

Gnomad SAS AF: 0.167

Gnomad FIN AF: 0.415

Gnomad MID AF: 0.303

Gnomad NFE AF: 0.282

Gnomad OTH AF: 0.266

GnomAD2 exomes AF: 0.119 AC: 17748 AN: 148610 AF XY: 0.109

Gnomad AFR exome AF: 0.0246

Gnomad AMR exome AF: 0.264

Gnomad ASJ exome AF: 0.0652

Gnomad EAS exome AF: 0.0963

Gnomad FIN exome AF: 0.180

Gnomad NFE exome AF: 0.102

Gnomad OTH exome AF: 0.104

GnomAD4 exome AF: 0.113 AC: 147549 AN: 1301506 Hom.: 8907 Cov.: 30 AF XY: 0.111 AC XY: 71045 AN XY: 641998

African (AFR) AF: 0.0250 AC: 732 AN: 29308

American (AMR) AF: 0.264 AC: 9039 AN: 34302

Ashkenazi Jewish (ASJ) AF: 0.0660 AC: 1438 AN: 21802

East Asian (EAS) AF: 0.102 AC: 3030 AN: 29644

South Asian (SAS) AF: 0.0489 AC: 3853 AN: 78758

European-Finnish (FIN) AF: 0.201 AC: 6637 AN: 33086

Middle Eastern (MID) AF: 0.0748 AC: 269 AN: 3594

European-Non Finnish (NFE) AF: 0.115 AC: 117050 AN: 1018912

Other (OTH) AF: 0.106 AC: 5501 AN: 52100

GnomAD4 genome AF: 0.275 AC: 14016 AN: 51038 Hom.: 934 Cov.: 0 AF XY: 0.275 AC XY: 7109 AN XY: 25878

African (AFR) AF: 0.116 AC: 1069 AN: 9244

American (AMR) AF: 0.399 AC: 2697 AN: 6754

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 183 AN: 992

East Asian (EAS) AF: 0.256 AC: 445 AN: 1736

South Asian (SAS) AF: 0.169 AC: 217 AN: 1284

European-Finnish (FIN) AF: 0.415 AC: 1932 AN: 4652

Middle Eastern (MID) AF: 0.295 AC: 33 AN: 112

European-Non Finnish (NFE) AF: 0.281 AC: 7055 AN: 25064

Other (OTH) AF: 0.262 AC: 191 AN: 728

Alfa AF: 0.0984 Hom.: 2271

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 18, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.5
DANN	Benign	0.72
PhyloP100		-0.44
Mutation Taster		=100/0	polymorphism (auto)

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: rs4653695; hg19: chr1-226033083;