rs35484156

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000358432.8(EPHA2):c.830C>T(p.Ser277Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00531 in 1,613,576 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0030 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0055 ( 34 hom. )

Consequence

EPHA2
ENST00000358432.8 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.396

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007756233).

BP6

Variant 1-16138424-G-A is Benign according to our data. Variant chr1-16138424-G-A is described in ClinVar as [Benign]. Clinvar id is 293440.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00301 (459/152288) while in subpopulation NFE AF= 0.0054 (367/68012). AF 95% confidence interval is 0.00494. There are 0 homozygotes in gnomad4. There are 196 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 459 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPHA2	NM_004431.5 linkuse as main transcript	c.830C>T	p.Ser277Leu	missense_variant	4/17	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.830C>T	p.Ser277Leu	missense_variant	4/17	1	NM_004431.5	ENSP00000351209	P1	P29317-1
EPHA2	ENST00000480202.1 linkuse as main transcript	n.35C>T		non_coding_transcript_exon_variant	2/6	5

Frequencies

GnomAD3 genomes

AF:

0.00302

AC:

459

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00126

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00170

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00540

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00321

AC:

800

AN:

249594

Hom.:

AF XY:

0.00335

AC XY:

453

AN XY:

135300

show subpopulations

Gnomad AFR exome

AF:

0.000685

Gnomad AMR exome

AF:

0.00127

Gnomad ASJ exome

AF:

0.000300

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00164

Gnomad FIN exome

AF:

0.00223

Gnomad NFE exome

AF:

0.00543

Gnomad OTH exome

AF:

0.00542

GnomAD4 exome

AF:

0.00555

AC:

8103

AN:

1461288

Hom.:

Cov.:

AF XY:

0.00539

AC XY:

3921

AN XY:

726918

show subpopulations

Gnomad4 AFR exome

AF:

0.000986

Gnomad4 AMR exome

AF:

0.00136

Gnomad4 ASJ exome

AF:

0.000306

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00189

Gnomad4 FIN exome

AF:

0.00254

Gnomad4 NFE exome

AF:

0.00672

Gnomad4 OTH exome

AF:

0.00368

GnomAD4 genome

AF:

0.00301

AC:

459

AN:

152288

Hom.:

Cov.:

AF XY:

0.00263

AC XY:

196

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.00125

Gnomad4 AMR

AF:

0.000719

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.00170

Gnomad4 NFE

AF:

0.00540

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00510

Hom.:

Bravo

AF:

0.00295

TwinsUK

AF:

0.00701

AC:

ALSPAC

AF:

0.00778

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00500

AC:

ExAC

AF:

0.00316

AC:

384

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00480

EpiControl

AF:

0.00510

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 06, 2020	- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 14, 2020

This variant is associated with the following publications: (PMID: 19649315) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.31

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.37

LIST_S2

Benign

0.72

M_CAP

Benign

0.042

MetaRNN

Benign

0.0078

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

MutationTaster

Benign

1.0

PrimateAI

Benign

0.34

PROVEAN

Benign

-2.1

REVEL

Benign

0.059

Sift

Benign

0.075

Sift4G

Benign

0.16

Polyphen

0.056

Vest4

0.22

MVP

0.46

MPC

0.12

ClinPred

0.013

GERP RS

4.2

Varity_R

0.19

gMVP

0.52

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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