rs2291804

Variant summary

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

The NM_004431.5(EPHA2):c.824-11G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.023 in 1,613,248 control chromosomes in the GnomAD database, including 524 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 41 hom., cov: 33)

Exomes 𝑓: 0.023 ( 483 hom. )

Consequence

EPHA2
NM_004431.5 splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.006032

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.0490

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 (BayesDel_noAF=-0.74).

BP6

Variant 1-16138441-C-T is Benign according to our data. Variant chr1-16138441-C-T is described in ClinVar as [Benign]. Clinvar id is 259396.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-16138441-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0184 (2799/152318) while in subpopulation SAS AF= 0.0476 (230/4828). AF 95% confidence interval is 0.0426. There are 41 homozygotes in gnomad4. There are 1471 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High AC in GnomAd at 2806 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPHA2	NM_004431.5 linkuse as main transcript	c.824-11G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000358432.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPHA2	ENST00000358432.8 linkuse as main transcript	c.824-11G>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_004431.5	P1	P29317-1
EPHA2	ENST00000480202.1 linkuse as main transcript	n.29-11G>A		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0184

AC:

2806

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00381

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0112

Gnomad ASJ

AF:

0.0251

Gnomad EAS

AF:

0.0262

Gnomad SAS

AF:

0.0474

Gnomad FIN

AF:

0.0424

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0225

Gnomad OTH

AF:

0.0167

GnomAD3 exomes

AF:

0.0252

AC:

6272

AN:

248464

Hom.:

112

AF XY:

0.0263

AC XY:

3548

AN XY:

134806

show subpopulations

Gnomad AFR exome

AF:

0.00325

Gnomad AMR exome

AF:

0.00983

Gnomad ASJ exome

AF:

0.0231

Gnomad EAS exome

AF:

0.0282

Gnomad SAS exome

AF:

0.0489

Gnomad FIN exome

AF:

0.0425

Gnomad NFE exome

AF:

0.0229

Gnomad OTH exome

AF:

0.0299

GnomAD4 exome

AF:

0.0235

AC:

34276

AN:

1460930

Hom.:

483

Cov.:

AF XY:

0.0242

AC XY:

17609

AN XY:

726684

show subpopulations

Gnomad4 AFR exome

AF:

0.00326

Gnomad4 AMR exome

AF:

0.00973

Gnomad4 ASJ exome

AF:

0.0227

Gnomad4 EAS exome

AF:

0.0280

Gnomad4 SAS exome

AF:

0.0457

Gnomad4 FIN exome

AF:

0.0420

Gnomad4 NFE exome

AF:

0.0218

Gnomad4 OTH exome

AF:

0.0238

GnomAD4 genome

AF:

0.0184

AC:

2799

AN:

152318

Hom.:

Cov.:

AF XY:

0.0198

AC XY:

1471

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00380

Gnomad4 AMR

AF:

0.0111

Gnomad4 ASJ

AF:

0.0251

Gnomad4 EAS

AF:

0.0258

Gnomad4 SAS

AF:

0.0476

Gnomad4 FIN

AF:

0.0424

Gnomad4 NFE

AF:

0.0225

Gnomad4 OTH

AF:

0.0161

Alfa

AF:

0.0212

Hom.:

Bravo

AF:

0.0153

Asia WGS

AF:

0.0560

AC:

196

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

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 13, 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	Invitae	Jan 21, 2024	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 11, 2021

This variant is associated with the following publications: (PMID: 28881807) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

Cadd

Benign

8.0

Dann

Benign

0.69

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0060

dbscSNV1_RF

Benign

0.098

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