1-16125329-C-T

Position:

• chr1-16125329-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_004431.5(EPHA2):​c.2826-9G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 25)
• Consequence: EPHA2 NM_004431.5 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.9984
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: -1.43

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 Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 1-16125329-C-T is Pathogenic according to our data. Variant chr1-16125329-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 280146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-16125329-C-T is described in Lovd as [Likely_pathogenic]. Variant chr1-16125329-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPHA2	NM_004431.5	c.2826-9G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000358432.8	NP_004422.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPHA2	ENST00000358432.8	c.2826-9G>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_004431.5	ENSP00000351209	P1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 25

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cataract 6 multiple types Pathogenic:3

Likely pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 13, 2020	This sequence change falls in intron 16 of the EPHA2 gene. It does not directly change the encoded amino acid sequence of the EPHA2 protein. This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. Experimental studies using a mini-gene assay reported that this variant causes  aberrant splicing resulting in a protein product that extends the carboxy-terminal SAM domain by 71 amino acid residues (PMID: 19306328). This extension alters EPHA2 protein solubility, intracellular localization, protein-protein interaction, and the ability to induce the phosphorylation of Akt kinase (PMID: 19306328, 22570727, 26900323). This variant has been reported to segregate with autosomal dominant congenital cataracts in several families (PMID: 19306328, 24014202). ClinVar contains an entry for this variant (Variation ID: 280146). -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2009	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 29, 2024

The c.2826-9G>A intronic alteration results from a G to A substitution 9 nucleotides before coding exon 17 in the EPHA2 gene. for autosomal dominant EPHA2-related cataract; however, its clinical significance for autosomal recessive EPHA2-related cataract is uncertain. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been found to segregate with affected individuals in multiple families with autosomal dominant congenital cataract (Zhang, 2009; Dave, 2013; Astiazarán, 2018; Berry, 2018). This nucleotide position is poorly conserved in available vertebrate species. A minigene assay confirmed that c.2826-9G>A results in aberrant splicing (Zhang, 2009). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. Based on the available evidence, this alteration is classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 16, 2021

Non-canonical splice site variant demonstrated to result in loss-of-function (Zhang et al, 2009); Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 30450742, 29039721, 33671840, 22570727, 26900323, 19306328, 24014202) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	21
DANN	Benign	0.74
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.92
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		1.0		Position offset: -2
DS_AL_spliceai		0.71		Position offset: -9

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs886041412; hg19: chr1-16451824;