3-89342065-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_005233.6(EPHA3):c.1281G>A(p.Ala427=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00488 in 1,609,542 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0037 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0050 (25 hom.)
• Consequence: EPHA3 NM_005233.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.23

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 Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 3-89342065-G-A is Benign according to our data. Variant chr3-89342065-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2653989.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.23 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome at 6 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPHA3	NM_005233.6	c.1281G>A	p.Ala427=	synonymous_variant	5/17	ENST00000336596.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPHA3	ENST00000336596.7	c.1281G>A	p.Ala427=	synonymous_variant	5/17	1	NM_005233.6	P1
EPHA3	ENST00000494014.1	c.1281G>A	p.Ala427=	synonymous_variant	5/17	1
EPHA3	ENST00000452448.6	c.1281G>A	p.Ala427=	synonymous_variant	5/7	1

Frequencies

GnomAD3 genomes AF: 0.00372 AC: 550 AN: 147736 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00100

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00198

Gnomad ASJ AF: 0.000584

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00454

Gnomad FIN AF: 0.00990

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00525

Gnomad OTH AF: 0.00348

GnomAD3 exomes AF: 0.00499 AC: 1242 AN: 248954 Hom.: 6 AF XY: 0.00512 AC XY: 690 AN XY: 134722

Gnomad AFR exome AF: 0.000985

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00546

Gnomad FIN exome AF: 0.00973

Gnomad NFE exome AF: 0.00693

Gnomad OTH exome AF: 0.00343

GnomAD4 exome AF: 0.00500 AC: 7311 AN: 1461688 Hom.: 25 Cov.: 31 AF XY: 0.00502 AC XY: 3649 AN XY: 727134

Gnomad4 AFR exome AF: 0.000986

Gnomad4 AMR exome AF: 0.00143

Gnomad4 ASJ exome AF: 0.00218

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00580

Gnomad4 FIN exome AF: 0.00910

Gnomad4 NFE exome AF: 0.00535

Gnomad4 OTH exome AF: 0.00348

GnomAD4 genome AF: 0.00371 AC: 549 AN: 147854 Hom.: 1 Cov.: 31 AF XY: 0.00400 AC XY: 287 AN XY: 71792

Gnomad4 AFR AF: 0.00100

Gnomad4 AMR AF: 0.00198

Gnomad4 ASJ AF: 0.000584

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00432

Gnomad4 FIN AF: 0.00990

Gnomad4 NFE AF: 0.00525

Gnomad4 OTH AF: 0.00344

Alfa AF: 0.00465 Hom.: 0

Bravo AF: 0.00325

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2023

EPHA3: BP4, BP7, BS2 -

EPHA3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 30, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	6.6
Dann	Benign	0.65

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: rs56112995; hg19: chr3-89391215; COSMIC: COSV60710820;