3-89472575-T-C

Variant names:

• chr3-89472575-T-C
• rs1054750
• NM_005233.6:c.2802T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_005233.6(EPHA3):​c.2802T>C​(p.Gly934Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.227 in 1,613,026 control chromosomes in the GnomAD database, including 45,489 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.19 (3374 hom., cov: 32)
  • Exomes 𝑓: 0.23 (42115 hom.)
• Consequence: EPHA3 NM_005233.6 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -2.25
• Publications: 22 publications found

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

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 3-89472575-T-C is Benign according to our data. Variant chr3-89472575-T-C is described in ClinVar as Benign. ClinVar VariationId is 3055487.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-2.25 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.242 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPHA3	NM_005233.6	c.2802T>C	p.Gly934Gly	synonymous_variant	Exon 16 of 17	ENST00000336596.7	NP_005224.2
EPHA3	XM_005264715.4	c.2799T>C	p.Gly933Gly	synonymous_variant	Exon 16 of 17		XP_005264772.1
EPHA3	NM_001410778.1	c.2749+53T>C		intron_variant	Intron 16 of 16		NP_001397707.1
EPHA3	XM_047447673.1	c.2746+53T>C		intron_variant	Intron 16 of 16		XP_047303629.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPHA3	ENST00000336596.7	c.2802T>C	p.Gly934Gly	synonymous_variant	Exon 16 of 17	1	NM_005233.6	ENSP00000337451.2
EPHA3	ENST00000494014.1	c.2749+53T>C		intron_variant	Intron 16 of 16	1		ENSP00000419190.1

Frequencies

GnomAD3 genomes AF: 0.191 AC: 29051 AN: 151974 Hom.: 3373 Cov.: 32

Gnomad AFR AF: 0.0915

Gnomad AMI AF: 0.0669

Gnomad AMR AF: 0.189

Gnomad ASJ AF: 0.154

Gnomad EAS AF: 0.0787

Gnomad SAS AF: 0.0840

Gnomad FIN AF: 0.368

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.246

Gnomad OTH AF: 0.171

GnomAD2 exomes AF: 0.204 AC: 51156 AN: 250650 AF XY: 0.201

Gnomad AFR exome AF: 0.0879

Gnomad AMR exome AF: 0.208

Gnomad ASJ exome AF: 0.143

Gnomad EAS exome AF: 0.0825

Gnomad FIN exome AF: 0.366

Gnomad NFE exome AF: 0.244

Gnomad OTH exome AF: 0.226

GnomAD4 exome AF: 0.231 AC: 337281 AN: 1460934 Hom.: 42115 Cov.: 34 AF XY: 0.227 AC XY: 164825 AN XY: 726800

African (AFR) AF: 0.0827 AC: 2767 AN: 33464

American (AMR) AF: 0.206 AC: 9215 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.145 AC: 3798 AN: 26112

East Asian (EAS) AF: 0.0597 AC: 2369 AN: 39692

South Asian (SAS) AF: 0.0912 AC: 7860 AN: 86184

European-Finnish (FIN) AF: 0.360 AC: 19216 AN: 53352

Middle Eastern (MID) AF: 0.106 AC: 612 AN: 5768

European-Non Finnish (NFE) AF: 0.251 AC: 279139 AN: 1111356

Other (OTH) AF: 0.204 AC: 12305 AN: 60352

GnomAD4 genome AF: 0.191 AC: 29061 AN: 152092 Hom.: 3374 Cov.: 32 AF XY: 0.192 AC XY: 14304 AN XY: 74348

African (AFR) AF: 0.0916 AC: 3800 AN: 41492

American (AMR) AF: 0.189 AC: 2887 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.154 AC: 536 AN: 3472

East Asian (EAS) AF: 0.0791 AC: 409 AN: 5172

South Asian (SAS) AF: 0.0839 AC: 405 AN: 4828

European-Finnish (FIN) AF: 0.368 AC: 3883 AN: 10542

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.246 AC: 16694 AN: 67988

Other (OTH) AF: 0.168 AC: 353 AN: 2104

Alfa AF: 0.213 Hom.: 6854

Bravo AF: 0.176

Asia WGS AF: 0.0810 AC: 281 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

EPHA3-related disorder Benign:1

Jun 19, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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	-0.62
CADD	Benign	3.1
DANN	Benign	0.68
PhyloP100		-2.3
Mutation Taster		=94/6	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1054750; hg19: chr3-89521725; COSMIC: COSV60692568;