1-16139508-T-C

Variant names:

• chr1-16139508-T-C
• rs11260745
• NM_004431.5:c.824-1078A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004431.5(EPHA2):​c.824-1078A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.139 in 152,110 control chromosomes in the GnomAD database, including 2,534 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.14 (2534 hom., cov: 33)
• Consequence: EPHA2 NM_004431.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.944
• Publications: 5 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.321 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPHA2	NM_004431.5	c.824-1078A>G		intron_variant	Intron 3 of 16	ENST00000358432.8	NP_004422.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPHA2	ENST00000358432.8	c.824-1078A>G		intron_variant	Intron 3 of 16	1	NM_004431.5	ENSP00000351209.5
EPHA2	ENST00000480202.1	n.29-1078A>G		intron_variant	Intron 1 of 5	5

Frequencies

GnomAD3 genomes AF: 0.139 AC: 21072 AN: 151992 Hom.: 2527 Cov.: 33

Gnomad AFR AF: 0.326

Gnomad AMI AF: 0.152

Gnomad AMR AF: 0.0926

Gnomad ASJ AF: 0.0652

Gnomad EAS AF: 0.121

Gnomad SAS AF: 0.124

Gnomad FIN AF: 0.0922

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0495

Gnomad OTH AF: 0.118

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

GnomAD4 genome AF: 0.139 AC: 21113 AN: 152110 Hom.: 2534 Cov.: 33 AF XY: 0.140 AC XY: 10395 AN XY: 74364

African (AFR) AF: 0.326 AC: 13501 AN: 41460

American (AMR) AF: 0.0928 AC: 1419 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0652 AC: 226 AN: 3468

East Asian (EAS) AF: 0.120 AC: 622 AN: 5162

South Asian (SAS) AF: 0.124 AC: 595 AN: 4814

European-Finnish (FIN) AF: 0.0922 AC: 978 AN: 10602

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0494 AC: 3361 AN: 67990

Other (OTH) AF: 0.117 AC: 248 AN: 2112

Alfa AF: 0.0791 Hom.: 3051

Bravo AF: 0.149

Asia WGS AF: 0.171 AC: 594 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.9
DANN	Benign	0.60
PhyloP100		0.94
Mutation Taster		=100/0	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: rs11260745; hg19: chr1-16466003;