Genetic Variant EPHA2:p.Ile976MetfsTer36 (chr1-16125216-CAG-C) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_004431.5(EPHA2):c.2928_2929delCT(p.Ile976MetfsTer36) variant causes a frameshift, stop lost change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

EPHA2
NM_004431.5 frameshift, stop_lost

Scores

Not classified

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 6.29

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Stoplost variant. No alternative stopcodon identified downstream, so we assume a Nonstop Mediated Decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-16125216-CAG-C is Pathogenic according to our data. Variant chr1-16125216-CAG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2633255.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPHA2	NM_004431.5 link	c.2928_2929delCT	p.Ile976MetfsTer36	frameshift_variant, stop_lost	Exon 17 of 17	ENST00000358432.8	NP_004422.2	P29317-1A0A024QZA8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPHA2	ENST00000358432.8 link	c.2928_2929delCT	p.Ile976MetfsTer36	frameshift_variant, stop_lost	Exon 17 of 17	1	NM_004431.5	ENSP00000351209.5		P29317-1

Frequencies

GnomAD3 genomes

Cov.:

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

EPHA2-related disorder

Pathogenic:1

May 12, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The EPHA2 c.2928_2929delCT variant is predicted to result in a frameshift and premature protein termination (p.Ile976Metfs*36). This variant disrupts the stop codon of the EPHA2 gene and leads to extension of the coding sequence by 36 amino acids. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Of note other variants leading to frameshifts and extension of the EPHA2 protein have been reported in patients with cataracts. (p.Ile976Hisfs*37 reported in Reis et al. 2014. PubMed ID: 24940039; p.Val972Glyfs*40 reported in Zhang et al. 2009. PubMed ID: 19306328). Frameshift variants in EPHA2 are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing