3-89395855-C-T

Variant summary

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

The NM_005233.6(EPHA3):c.1325C>T(p.Thr442Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000799 in 1,613,982 control chromosomes in the GnomAD database, including 1 homozygotes. 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: 𝑓 0.00033 (1 hom., cov: 33)
  • Exomes 𝑓: 0.000054 (0 hom.)
• Consequence: EPHA3 NM_005233.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.72

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 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=0.035794437).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPHA3	NM_005233.6	c.1325C>T	p.Thr442Met	missense_variant	6/17	ENST00000336596.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPHA3	ENST00000336596.7	c.1325C>T	p.Thr442Met	missense_variant	6/17	1	NM_005233.6	P1
EPHA3	ENST00000494014.1	c.1325C>T	p.Thr442Met	missense_variant	6/17	1
EPHA3	ENST00000452448.6	c.1325C>T	p.Thr442Met	missense_variant	6/7	1

Frequencies

GnomAD3 genomes AF: 0.000309 AC: 47 AN: 152146 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000990

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000107 AC: 27 AN: 251188 Hom.: 0 AF XY: 0.000125 AC XY: 17 AN XY: 135750

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000540 AC: 79 AN: 1461718 Hom.: 0 Cov.: 31 AF XY: 0.0000619 AC XY: 45 AN XY: 727142

Gnomad4 AFR exome AF: 0.00105

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.000414

GnomAD4 genome AF: 0.000328 AC: 50 AN: 152264 Hom.: 1 Cov.: 33 AF XY: 0.000403 AC XY: 30 AN XY: 74456

Gnomad4 AFR AF: 0.00106

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000125 Hom.: 0

Bravo AF: 0.000427

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000132 AC: 16

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

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

Sep 16, 2021

The c.1325C>T (p.T442M) alteration is located in exon 6 (coding exon 6) of the EPHA3 gene. This alteration results from a C to T substitution at nucleotide position 1325, causing the threonine (T) at amino acid position 442 to be replaced by a methionine (M). 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	0.067
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	19
Dann	Benign	0.94
DEOGEN2	Benign	0.078	T;.;.
Eigen	Benign	-0.049
Eigen_PC	Benign	0.052
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.86	D;D;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.036	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.38	N;N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.033
Sift	Benign	0.33	T;T;T
Sift4G	Benign	0.11	T;T;T
Polyphen		0.54	P;P;.
Vest4		0.40
MVP		0.62
MPC		0.26
ClinPred		0.016	T
GERP RS		2.9
Varity_R		0.044
gMVP		0.18

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: rs112239794; hg19: chr3-89445005; COSMIC: COSV60714709;