19-15231284-T-G

Position:

• chr19-15231284-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_024794.3(EPHX3):​c.442A>C​(p.Ile148Leu) 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 benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EPHX3 NM_024794.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.144

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.050512046).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPHX3	NM_024794.3	c.442A>C	p.Ile148Leu	missense_variant	3/7	ENST00000221730.8
EPHX3	NM_001142886.2	c.442A>C	p.Ile148Leu	missense_variant	4/8
EPHX3	XM_024451725.2	c.442A>C	p.Ile148Leu	missense_variant	5/9
EPHX3	XM_047439452.1	c.442A>C	p.Ile148Leu	missense_variant	5/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPHX3	ENST00000221730.8	c.442A>C	p.Ile148Leu	missense_variant	3/7	1	NM_024794.3	P1
EPHX3	ENST00000435261.5	c.442A>C	p.Ile148Leu	missense_variant	4/8	1		P1
EPHX3	ENST00000602233.5	c.442A>C	p.Ile148Leu	missense_variant	5/9	5		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

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

Nov 03, 2022

The c.442A>C (p.I148L) alteration is located in exon 3 (coding exon 3) of the EPHX3 gene. This alteration results from a A to C substitution at nucleotide position 442, causing the isoleucine (I) at amino acid position 148 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	0.070
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.54
DANN	Benign	0.50
DEOGEN2	Benign	0.024	T;T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.28	.;T;.
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.051	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.92	L;L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.21	N;N;.
REVEL	Benign	0.079
Sift	Benign	0.76	T;T;.
Sift4G	Benign	0.96	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.27
MutPred		0.56		Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);
MVP		0.11
MPC		0.17
ClinPred		0.092	T
GERP RS		2.1
Varity_R		0.036
gMVP		0.40

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: chr19-15342095;