chr1-16125329-C-T

Variant names:

• chr1-16125329-C-T
• rs886041412
• NM_004431.5:c.2826-9G>A

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS3 PM2 PP3 PP5_Very_Strong

The NM_004431.5(EPHA2):​c.2826-9G>A variant causes a 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 (★★). ClinVar reports functional evidence for this variant: "SCV000766128: 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)." and additional evidence is available in ClinVar.

• Frequency: Genomes: not found (cov: 25)
• Consequence: EPHA2 NM_004431.5 intron
• Scores: Splicing: ADA: 0.9984
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: -1.43
• Publications: 14 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), 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: Pathogenic. The variant received 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000766128: 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).; SCV005416604: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."; SCV005118908: A minigene assay confirmed that c.2826-9G>A results in aberrant splicing (Zhang, 2009).
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious 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 VariationId is 280146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004431.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPHA2	NM_004431.5	MANE Select	c.2826-9G>A		intron	N/A	NP_004422.2
	EPHA2	NM_001329090.2		c.2664-9G>A		intron	N/A	NP_001316019.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPHA2	ENST00000358432.8	TSL:1 MANE Select	c.2826-9G>A		intron	N/A	ENSP00000351209.5	P29317-1
	EPHA2	ENST00000917106.1		c.2841-9G>A		intron	N/A	ENSP00000587165.1
	EPHA2	ENST00000863593.1		c.2805-9G>A		intron	N/A	ENSP00000533652.1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 25

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	Cataract 6 multiple types (6)
1	-	-	Inborn genetic diseases (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	21
DANN	Benign	0.74
PhyloP100		-1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6
Mutation Taster		=37/63	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs886041412; hg19: chr1-16451824;