chr19-15230986-C-T

Position:

• chr19-15230986-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_024794.3(EPHX3):​c.592G>A​(p.Gly198Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 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)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: EPHX3 NM_024794.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.78

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPHX3	NM_024794.3	c.592G>A	p.Gly198Ser	missense_variant	4/7	ENST00000221730.8
EPHX3	NM_001142886.2	c.592G>A	p.Gly198Ser	missense_variant	5/8
EPHX3	XM_024451725.2	c.592G>A	p.Gly198Ser	missense_variant	6/9
EPHX3	XM_047439452.1	c.592G>A	p.Gly198Ser	missense_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPHX3	ENST00000221730.8	c.592G>A	p.Gly198Ser	missense_variant	4/7	1	NM_024794.3	P1
EPHX3	ENST00000435261.5	c.592G>A	p.Gly198Ser	missense_variant	5/8	1		P1
EPHX3	ENST00000602233.5	c.592G>A	p.Gly198Ser	missense_variant	6/9	5		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461760 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727166

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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 06, 2023

The c.592G>A (p.G198S) alteration is located in exon 4 (coding exon 4) of the EPHX3 gene. This alteration results from a G to A substitution at nucleotide position 592, causing the glycine (G) at amino acid position 198 to be replaced by a serine (S). 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	0.14
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	22
DANN	Benign	0.63
DEOGEN2	Benign	0.013	T;T;T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.78	.;T;.
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.28	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.58	N;N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.53	N;N;.
REVEL	Benign	0.15
Sift	Benign	0.47	T;T;.
Sift4G	Benign	0.42	T;T;T
Polyphen		0.013	B;B;B
Vest4		0.46
MVP		0.33
MPC		0.18
ClinPred		0.11	T
GERP RS		4.4
Varity_R		0.093
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.44		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.44		Position offset: 7

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs373910513; hg19: chr19-15341797;