1-16125242-C-G

Position:

chr1-16125242-C-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_004431.5(EPHA2):c.2904G>C(p.Gln968His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00241 in 1,613,984 control chromosomes in the GnomAD database, including 12 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0017 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0025 ( 12 hom. )

Consequence

EPHA2
NM_004431.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 0.361

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008738786).

BP6

Variant 1-16125242-C-G is Benign according to our data. Variant chr1-16125242-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 293406.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=1}. Variant chr1-16125242-C-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00172 (262/152290) while in subpopulation NFE AF= 0.00278 (189/68028). AF 95% confidence interval is 0.00245. There are 0 homozygotes in gnomad4. There are 128 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 262 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPHA2	NM_004431.5 linkuse as main transcript	c.2904G>C	p.Gln968His	missense_variant	17/17	ENST00000358432.8	NP_004422.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPHA2	ENST00000358432.8 linkuse as main transcript	c.2904G>C	p.Gln968His	missense_variant	17/17	1	NM_004431.5	ENSP00000351209	P1	P29317-1

Frequencies

GnomAD3 genomes

AF:

0.00172

AC:

261

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000627

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000982

Gnomad ASJ

AF:

0.00519

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.000753

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00278

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00187

AC:

467

AN:

250282

Hom.:

AF XY:

0.00184

AC XY:

249

AN XY:

135620

show subpopulations

Gnomad AFR exome

AF:

0.000248

Gnomad AMR exome

AF:

0.000811

Gnomad ASJ exome

AF:

0.00418

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000884

Gnomad FIN exome

AF:

0.000650

Gnomad NFE exome

AF:

0.00294

Gnomad OTH exome

AF:

0.00328

GnomAD4 exome

AF:

0.00248

AC:

3629

AN:

1461694

Hom.:

Cov.:

AF XY:

0.00244

AC XY:

1776

AN XY:

727124

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.000760

Gnomad4 ASJ exome

AF:

0.00459

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000986

Gnomad4 FIN exome

AF:

0.000506

Gnomad4 NFE exome

AF:

0.00288

Gnomad4 OTH exome

AF:

0.00240

GnomAD4 genome

AF:

0.00172

AC:

262

AN:

152290

Hom.:

Cov.:

AF XY:

0.00172

AC XY:

128

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.000626

Gnomad4 AMR

AF:

0.000981

Gnomad4 ASJ

AF:

0.00519

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000623

Gnomad4 FIN

AF:

0.000753

Gnomad4 NFE

AF:

0.00278

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00249

Hom.:

Bravo

AF:

0.00171

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00349

AC:

ExAC

AF:

0.00203

AC:

247

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00305

EpiControl

AF:

0.00326

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cataract 6 multiple types

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 28, 2023	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 06, 2016

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 29, 2018

- -

EPHA2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 17, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.13

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.82

M_CAP

Benign

0.036

MetaRNN

Benign

0.0087

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.3

MutationTaster

Benign

0.99

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.1

REVEL

Benign

0.18

Sift

Benign

0.082

Sift4G

Benign

0.11

Polyphen

0.031

Vest4

0.54

MutPred

0.73

Gain of ubiquitination at K966 (P = 0.0767);

MVP

0.77

MPC

0.62

ClinPred

0.018

GERP RS

-2.2

Varity_R

0.21

gMVP

0.90

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over