NM_004431.5:c.2874C>T

Variant names:

• chr1-16125272-G-A
• rs3754334
• NM_004431.5:c.2874C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004431.5(EPHA2):​c.2874C>T​(p.Ile958Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.273 in 1,613,100 control chromosomes in the GnomAD database, including 62,352 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (4945 hom., cov: 31)
  • Exomes 𝑓: 0.28 (57407 hom.)
• Consequence: EPHA2 NM_004431.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.42
• Publications: 36 publications found

Genes affected

EPHA2 (HGNC:3386): (EPH receptor A2) 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. Mutations in this gene are the cause of certain genetically-related cataract disorders.[provided by RefSeq, May 2010]

EPHA2 Gene-Disease associations (from GenCC):

• cataract 6 multiple types

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• early-onset non-syndromic cataract

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• early-onset nuclear cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset posterior polar cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset posterior subcapsular cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• total early-onset cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 1-16125272-G-A is Benign according to our data. Variant chr1-16125272-G-A is described in ClinVar as Benign. ClinVar VariationId is 259392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.41 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.343 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPHA2	NM_004431.5	c.2874C>T	p.Ile958Ile	synonymous_variant	Exon 17 of 17	ENST00000358432.8	NP_004422.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPHA2	ENST00000358432.8	c.2874C>T	p.Ile958Ile	synonymous_variant	Exon 17 of 17	1	NM_004431.5	ENSP00000351209.5

Frequencies

GnomAD3 genomes AF: 0.242 AC: 36763 AN: 151750 Hom.: 4943 Cov.: 31

Gnomad AFR AF: 0.130

Gnomad AMI AF: 0.473

Gnomad AMR AF: 0.322

Gnomad ASJ AF: 0.302

Gnomad EAS AF: 0.151

Gnomad SAS AF: 0.358

Gnomad FIN AF: 0.272

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.279

Gnomad OTH AF: 0.270

GnomAD2 exomes AF: 0.278 AC: 69557 AN: 250116 AF XY: 0.285

Gnomad AFR exome AF: 0.126

Gnomad AMR exome AF: 0.343

Gnomad ASJ exome AF: 0.286

Gnomad EAS exome AF: 0.146

Gnomad FIN exome AF: 0.264

Gnomad NFE exome AF: 0.281

Gnomad OTH exome AF: 0.293

GnomAD4 exome AF: 0.276 AC: 403401 AN: 1461232 Hom.: 57407 Cov.: 36 AF XY: 0.280 AC XY: 203228 AN XY: 726904

African (AFR) AF: 0.130 AC: 4337 AN: 33464

American (AMR) AF: 0.340 AC: 15175 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.290 AC: 7575 AN: 26122

East Asian (EAS) AF: 0.152 AC: 6037 AN: 39690

South Asian (SAS) AF: 0.354 AC: 30557 AN: 86206

European-Finnish (FIN) AF: 0.258 AC: 13767 AN: 53274

Middle Eastern (MID) AF: 0.353 AC: 2038 AN: 5768

European-Non Finnish (NFE) AF: 0.277 AC: 307577 AN: 1111656

Other (OTH) AF: 0.271 AC: 16338 AN: 60358

GnomAD4 genome AF: 0.242 AC: 36771 AN: 151868 Hom.: 4945 Cov.: 31 AF XY: 0.246 AC XY: 18288 AN XY: 74194

African (AFR) AF: 0.130 AC: 5399 AN: 41450

American (AMR) AF: 0.322 AC: 4920 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.302 AC: 1047 AN: 3466

East Asian (EAS) AF: 0.151 AC: 776 AN: 5130

South Asian (SAS) AF: 0.357 AC: 1716 AN: 4800

European-Finnish (FIN) AF: 0.272 AC: 2867 AN: 10530

Middle Eastern (MID) AF: 0.333 AC: 98 AN: 294

European-Non Finnish (NFE) AF: 0.279 AC: 18943 AN: 67910

Other (OTH) AF: 0.273 AC: 575 AN: 2106

Alfa AF: 0.268 Hom.: 23515

Bravo AF: 0.238

Asia WGS AF: 0.294 AC: 1024 AN: 3476

EpiCase AF: 0.293

EpiControl AF: 0.298

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cataract 6 multiple types Benign:3

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Apr 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	4.0
DANN	Benign	0.83
PhyloP100		-1.4
Mutation Taster		=98/2	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: rs3754334; hg19: chr1-16451767; COSMIC: COSV64453666;