19-15227627-G-A

Position:

• chr19-15227627-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_024794.3(EPHX3):​c.893C>T​(p.Pro298Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: EPHX3 NM_024794.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.77

Genes affected

EPHX3 (HGNC:23760): (epoxide hydrolase 3) Enables epoxide hydrolase activity. Involved in epoxide metabolic process. Located in intracellular membrane-bounded organelle and membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.783

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPHX3	NM_024794.3	c.893C>T	p.Pro298Leu	missense_variant	7/7	ENST00000221730.8
EPHX3	NM_001142886.2	c.893C>T	p.Pro298Leu	missense_variant	8/8
EPHX3	XM_024451725.2	c.893C>T	p.Pro298Leu	missense_variant	9/9
EPHX3	XM_047439452.1	c.893C>T	p.Pro298Leu	missense_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPHX3	ENST00000221730.8	c.893C>T	p.Pro298Leu	missense_variant	7/7	1	NM_024794.3	P1
EPHX3	ENST00000435261.5	c.893C>T	p.Pro298Leu	missense_variant	8/8	1		P1
EPHX3	ENST00000602233.5	c.893C>T	p.Pro298Leu	missense_variant	9/9	5		P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 13, 2023

The c.893C>T (p.P298L) alteration is located in exon 7 (coding exon 7) of the EPHX3 gene. This alteration results from a C to T substitution at nucleotide position 893, causing the proline (P) at amino acid position 298 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D;D;D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.80	D
M_CAP	Benign	0.054	D
MetaRNN	Pathogenic	0.78	D;D;D
MetaSVM	Benign	-0.33	T
MutationAssessor	Pathogenic	4.0	H;H;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-9.2	D;D;.
REVEL	Uncertain	0.31
Sift	Uncertain	0.0020	D;D;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.99	D;D;D
Vest4		0.56
MutPred		0.85		Loss of glycosylation at P298 (P = 0.0505);Loss of glycosylation at P298 (P = 0.0505);Loss of glycosylation at P298 (P = 0.0505);
MVP		0.38
MPC		0.70
ClinPred		1.0	D
GERP RS		1.1
Varity_R		0.48
gMVP		0.72

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-15338438;