3-89210044-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005233.6(EPHA3):c.338T>C(p.Leu113Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000279 in 1,614,054 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: EPHA3 NM_005233.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.13

Genes affected

EPHA3 (HGNC:3387): (EPH receptor A3) This gene belongs to the ephrin receptor subfamily of the protein-tyrosine kinase family. EPH and EPH-related receptors have been implicated in mediating developmental events, particularly in the nervous system. Receptors in the EPH subfamily typically have a single kinase domain and an extracellular region containing a Cys-rich domain and 2 fibronectin type III repeats. The ephrin receptors are divided into 2 groups based on the similarity of their extracellular domain sequences and their affinities for binding ephrin-A and ephrin-B ligands. This gene encodes a protein that binds ephrin-A ligands. Two alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12418732).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPHA3	NM_005233.6	c.338T>C	p.Leu113Ser	missense_variant	3/17	ENST00000336596.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPHA3	ENST00000336596.7	c.338T>C	p.Leu113Ser	missense_variant	3/17	1	NM_005233.6	P1
EPHA3	ENST00000494014.1	c.338T>C	p.Leu113Ser	missense_variant	3/17	1
EPHA3	ENST00000452448.6	c.338T>C	p.Leu113Ser	missense_variant	3/7	1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000716 AC: 18 AN: 251314 Hom.: 0 AF XY: 0.0000515 AC XY: 7 AN XY: 135824

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.0000274 AC: 40 AN: 1461760 Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13 AN XY: 727174

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000993

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152294 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74470

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000135 Hom.: 0

Bravo AF: 0.000102

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.0000546

EpiControl AF: 0.00

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

Jan 02, 2024

The c.338T>C (p.L113S) alteration is located in exon 3 (coding exon 3) of the EPHA3 gene. This alteration results from a T to C substitution at nucleotide position 338, causing the leucine (L) at amino acid position 113 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	0.24
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.087	T;.;.
Eigen	Benign	-0.035
Eigen_PC	Benign	0.065
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.67	T;T;T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	-0.020	N;N;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.50	N;N;N
REVEL	Benign	0.17
Sift	Benign	0.92	T;T;T
Sift4G	Benign	0.62	T;T;T
Polyphen		1.0	D;B;.
Vest4		0.65
MutPred		0.50		Gain of glycosylation at L113 (P = 0.0725);Gain of glycosylation at L113 (P = 0.0725);Gain of glycosylation at L113 (P = 0.0725);
MVP		0.63
MPC		0.90
ClinPred		0.24	T
GERP RS		3.2
Varity_R		0.19
gMVP		0.51

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

LitVar

Other links and lift over

dbSNP: rs537025827; hg19: chr3-89259194;