3-89407300-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6_Very_Strong BP7

The NM_005233.6(EPHA3):c.1626G>A(p.Val542=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00185 in 1,613,496 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (3 hom.)
• Consequence: EPHA3 NM_005233.6 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.129

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 3-89407300-G-A is Benign according to our data. Variant chr3-89407300-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 717834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.129 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPHA3	NM_005233.6	c.1626G>A	p.Val542=	synonymous_variant	8/17	ENST00000336596.7
EPHA3	NM_001410778.1	c.1626G>A	p.Val542=	synonymous_variant	8/17
EPHA3	XM_005264715.4	c.1623G>A	p.Val541=	synonymous_variant	8/17
EPHA3	XM_047447673.1	c.1623G>A	p.Val541=	synonymous_variant	8/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPHA3	ENST00000336596.7	c.1626G>A	p.Val542=	synonymous_variant	8/17	1	NM_005233.6	P1
EPHA3	ENST00000494014.1	c.1626G>A	p.Val542=	synonymous_variant	8/17	1

Frequencies

GnomAD3 genomes AF: 0.00130 AC: 198 AN: 152060 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000411

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00232

Gnomad OTH AF: 0.000959

GnomAD3 exomes AF: 0.00128 AC: 322 AN: 251188 Hom.: 0 AF XY: 0.00129 AC XY: 175 AN XY: 135770

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00148

Gnomad NFE exome AF: 0.00237

Gnomad OTH exome AF: 0.000979

GnomAD4 exome AF: 0.00191 AC: 2786 AN: 1461318 Hom.: 3 Cov.: 30 AF XY: 0.00187 AC XY: 1361 AN XY: 726958

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000425

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00129

Gnomad4 NFE exome AF: 0.00234

Gnomad4 OTH exome AF: 0.00141

GnomAD4 genome AF: 0.00130 AC: 198 AN: 152178 Hom.: 0 Cov.: 32 AF XY: 0.00112 AC XY: 83 AN XY: 74404

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.00232

Gnomad4 OTH AF: 0.000949

Alfa AF: 0.00172 Hom.: 0

Bravo AF: 0.00109

EpiCase AF: 0.00164

EpiControl AF: 0.00231

ClinVar

Significance: 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

Invitae

Jan 02, 2018

- -

EPHA3-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 28, 2019

This variant is classified as likely 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	-0.45
Cadd	Benign	4.8
Dann	Benign	0.53

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: rs56330723; hg19: chr3-89456450; COSMIC: COSV60722897;