chr1-16128557-C-T

Variant names:

• chr1-16128557-C-T
• rs11260721
• NM_004431.5:c.2825+877G>A

Variant summary

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

The NM_004431.5(EPHA2):​c.2825+877G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.707 in 152,212 control chromosomes in the GnomAD database, including 44,017 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 0.71 (44017 hom., cov: 33)
• Consequence: EPHA2 NM_004431.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.925
• Publications: 6 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=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.897 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPHA2	NM_004431.5	c.2825+877G>A		intron_variant	Intron 16 of 16	ENST00000358432.8	NP_004422.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPHA2	ENST00000358432.8	c.2825+877G>A		intron_variant	Intron 16 of 16	1	NM_004431.5	ENSP00000351209.5

Frequencies

GnomAD3 genomes AF: 0.708 AC: 107680 AN: 152094 Hom.: 44017 Cov.: 33

Gnomad AFR AF: 0.264

Gnomad AMI AF: 0.831

Gnomad AMR AF: 0.823

Gnomad ASJ AF: 0.865

Gnomad EAS AF: 0.751

Gnomad SAS AF: 0.803

Gnomad FIN AF: 0.883

Gnomad MID AF: 0.877

Gnomad NFE AF: 0.903

Gnomad OTH AF: 0.750

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

GnomAD4 genome AF: 0.707 AC: 107688 AN: 152212 Hom.: 44017 Cov.: 33 AF XY: 0.709 AC XY: 52744 AN XY: 74424

African (AFR) AF: 0.263 AC: 10921 AN: 41498

American (AMR) AF: 0.823 AC: 12602 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.865 AC: 3002 AN: 3470

East Asian (EAS) AF: 0.752 AC: 3890 AN: 5176

South Asian (SAS) AF: 0.803 AC: 3871 AN: 4820

European-Finnish (FIN) AF: 0.883 AC: 9368 AN: 10608

Middle Eastern (MID) AF: 0.867 AC: 255 AN: 294

European-Non Finnish (NFE) AF: 0.903 AC: 61439 AN: 68014

Other (OTH) AF: 0.748 AC: 1582 AN: 2114

Alfa AF: 0.822 Hom.: 36277

Bravo AF: 0.683

Asia WGS AF: 0.678 AC: 2360 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.22
DANN	Benign	0.48
PhyloP100		-0.93
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: rs11260721; hg19: chr1-16455052;