rs3754334

Positions:

• chr1-16125272-G-A
• chr1-16125272-G-C

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 259392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-16125272-G-A is described in Lovd as [Benign]. Variant chr1-16125272-G-A is described in Lovd as [Likely_benign].
• 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/exons	MANE	Protein	UniProt
EPHA2	NM_004431.5	c.2874C>T	p.Ile958Ile	synonymous_variant	17/17	ENST00000358432.8	NP_004422.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPHA2	ENST00000358432.8	c.2874C>T	p.Ile958Ile	synonymous_variant	17/17	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

GnomAD3 exomes AF: 0.278 AC: 69557 AN: 250116 Hom.: 10305 AF XY: 0.285 AC XY: 38649 AN XY: 135512

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 SAS exome AF: 0.360

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

Gnomad4 AFR exome AF: 0.130

Gnomad4 AMR exome AF: 0.340

Gnomad4 ASJ exome AF: 0.290

Gnomad4 EAS exome AF: 0.152

Gnomad4 SAS exome AF: 0.354

Gnomad4 FIN exome AF: 0.258

Gnomad4 NFE exome AF: 0.277

Gnomad4 OTH exome AF: 0.271

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

Gnomad4 AFR AF: 0.130

Gnomad4 AMR AF: 0.322

Gnomad4 ASJ AF: 0.302

Gnomad4 EAS AF: 0.151

Gnomad4 SAS AF: 0.357

Gnomad4 FIN AF: 0.272

Gnomad4 NFE AF: 0.279

Gnomad4 OTH AF: 0.273

Alfa AF: 0.273 Hom.: 12518

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

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 12, 2018	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. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	4.0
DANN	Benign	0.83

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: rs3754334; hg19: chr1-16451767; COSMIC: COSV64453666;