rs72549341

Variant names:

• chr1-225844578-A-C
• rs72549341
• NM_001136018.4:c.1121A>C

Your query was ambiguous. Multiple possible variants found:

• chr1-225844578-A-C
• chr1-225844578-A-G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_001136018.4(EPHX1):​c.1121A>C​(p.Tyr374Ser) variant causes a missense change involving the alteration of a 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.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EPHX1 NM_001136018.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.28
• Publications: 2 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, Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a active_site Proton donor (size 0) in uniprot entity HYEP_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPHX1	NM_001136018.4	MANE Select	c.1121A>C	p.Tyr374Ser	missense	Exon 8 of 9	NP_001129490.1	R4SBI6
	EPHX1	NM_000120.4		c.1121A>C	p.Tyr374Ser	missense	Exon 8 of 9	NP_000111.1	R4SBI6
	EPHX1	NM_001291163.2		c.1121A>C	p.Tyr374Ser	missense	Exon 8 of 9	NP_001278092.1	P07099

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPHX1	ENST00000272167.10	TSL:1 MANE Select	c.1121A>C	p.Tyr374Ser	missense	Exon 8 of 9	ENSP00000272167.5	P07099
	EPHX1	ENST00000366837.5	TSL:1	c.1121A>C	p.Tyr374Ser	missense	Exon 8 of 9	ENSP00000355802.4	P07099
	EPHX1	ENST00000614058.4	TSL:1	c.1121A>C	p.Tyr374Ser	missense	Exon 8 of 9	ENSP00000480004.1	P07099

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.85	D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.041	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Benign	-0.39	T
MutationAssessor	Pathogenic	4.2	H
PhyloP100		7.3
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-8.4	D
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.80		Gain of disorder (P = 0.0023)
MVP		0.61
MPC		0.92
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.95
gMVP		0.97
Mutation Taster		=23/77	disease causing

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: rs72549341; hg19: chr1-226032279;