rs1051741

Variant names:

• chr1-225844528-C-T
• rs1051741
• NM_001136018.4:c.1071C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.102
• Publications: 49 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 -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPHX1	NM_001136018.4	c.1071C>T	p.Asn357Asn	synonymous_variant	Exon 8 of 9	ENST00000272167.10	NP_001129490.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPHX1	ENST00000272167.10	c.1071C>T	p.Asn357Asn	synonymous_variant	Exon 8 of 9	1	NM_001136018.4	ENSP00000272167.5
EPHX1	ENST00000366837.5	c.1071C>T	p.Asn357Asn	synonymous_variant	Exon 8 of 9	1		ENSP00000355802.4
EPHX1	ENST00000614058.4	c.1071C>T	p.Asn357Asn	synonymous_variant	Exon 8 of 9	1		ENSP00000480004.1
ENSG00000242861	ENST00000424332.1	n.43+1952G>A		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes AF: 0.0989 AC: 15037 AN: 152062 Hom.: 850 Cov.: 32

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

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.: 33 AF XY: 0.110 AC XY: 79966 AN XY: 727234

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

GnomAD4 genome AF: 0.0989 AC: 15047 AN: 152180 Hom.: 851 Cov.: 32 AF XY: 0.0975 AC XY: 7254 AN XY: 74392

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: 30 AN: 294

European-Non Finnish (NFE) AF: 0.0976 AC: 6632 AN: 67980

Other (OTH) AF: 0.106 AC: 223 AN: 2112

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

Submissions by phenotype

not provided Benign:2

Nov 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	14
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)

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

Other links and lift over

dbSNP: rs1051741; hg19: chr1-226032229; COSMIC: COSV55299610; COSMIC: COSV55299610;