1-16137994-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004431.5(EPHA2):c.1171G>A(p.Gly391Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0176 in 1,614,014 control chromosomes in the GnomAD database, including 509 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 55 hom., cov: 32)

Exomes 𝑓: 0.018 ( 454 hom. )

Consequence

EPHA2
NM_004431.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.0730

Publications

40 publications found

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 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

EPHA2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0030229986).

BP6

Variant 1-16137994-C-T is Benign according to our data. Variant chr1-16137994-C-T is described in ClinVar as [Benign]. Clinvar id is 259386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0623 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPHA2	NM_004431.5 link	c.1171G>A	p.Gly391Arg	missense_variant	Exon 5 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.1171G>A	p.Gly391Arg	missense_variant	Exon 5 of 17	1	NM_004431.5	ENSP00000351209.5		P29317-1
EPHA2	ENST00000480202.1 link	n.376G>A		non_coding_transcript_exon_variant	Exon 3 of 6	5

Frequencies

GnomAD3 genomes

AF:

0.0166

AC:

2531

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00393

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0656

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.0145

Gnomad FIN

AF:

0.00809

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0170

Gnomad OTH

AF:

0.0186

GnomAD2 exomes

AF:

0.0246

AC:

6175

AN:

250856

AF XY:

0.0223

show subpopulations

Gnomad AFR exome

AF:

0.00376

Gnomad AMR exome

AF:

0.102

Gnomad ASJ exome

AF:

0.00427

Gnomad EAS exome

AF:

0.00114

Gnomad FIN exome

AF:

0.00952

Gnomad NFE exome

AF:

0.0151

Gnomad OTH exome

AF:

0.0208

GnomAD4 exome

AF:

0.0177

AC:

25847

AN:

1461658

Hom.:

454

Cov.:

AF XY:

0.0174

AC XY:

12687

AN XY:

727134

show subpopulations

African (AFR)

AF:

0.00293

AC:

AN:

33480

American (AMR)

AF:

0.0969

AC:

4330

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.00360

AC:

AN:

26136

East Asian (EAS)

AF:

0.000630

AC:

AN:

39696

South Asian (SAS)

AF:

0.0149

AC:

1281

AN:

86256

European-Finnish (FIN)

AF:

0.00960

AC:

511

AN:

53242

Middle Eastern (MID)

AF:

0.00538

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0168

AC:

18653

AN:

1111998

Other (OTH)

AF:

0.0136

AC:

824

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

1986

3972

5959

7945

9931

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0166

AC:

2533

AN:

152356

Hom.:

Cov.:

AF XY:

0.0165

AC XY:

1232

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.00392

AC:

163

AN:

41584

American (AMR)

AF:

0.0657

AC:

1005

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00317

AC:

AN:

3468

East Asian (EAS)

AF:

0.000578

AC:

AN:

5186

South Asian (SAS)

AF:

0.0145

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00809

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0170

AC:

1156

AN:

68034

Other (OTH)

AF:

0.0184

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

132

265

397

530

662

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0164

Hom.:

102

Bravo

AF:

0.0202

TwinsUK

AF:

0.0140

AC:

ALSPAC

AF:

0.0174

AC:

ESP6500AA

AF:

0.00318

AC:

ESP6500EA

AF:

0.0173

AC:

149

ExAC

AF:

0.0209

AC:

2541

Asia WGS

AF:

0.00664

AC:

AN:

3478

EpiCase

AF:

0.0142

EpiControl

AF:

0.0142

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cataract 6 multiple types

Benign:3

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jan 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 20, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

not provided

Benign:2

Oct 01, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.54

CADD

Benign

8.2

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.31

Eigen

Benign

-0.94

Eigen_PC

Benign

-0.98

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.15

MetaRNN

Benign

0.0030

MetaSVM

Benign

-0.94

MutationAssessor

Uncertain

2.2

PhyloP100

0.073

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-4.1

REVEL

Benign

0.12

Sift

Uncertain

0.017

Sift4G

Benign

0.073

Polyphen

0.0010

Vest4

0.088

MutPred

0.30

Gain of solvent accessibility (P = 0.0456);

MPC

0.16

ClinPred

0.026

GERP RS

2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.26

gMVP

0.51

Mutation Taster

=97/3

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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1-16137994-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over