rs55655135

chr1-16133337-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004431.5(EPHA2):c.1896G>A(p.Leu632=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00743 in 1,613,868 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0077 (51 hom.)
• Consequence: EPHA2 NM_004431.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.65

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 1-16133337-C-T is Benign according to our data. Variant chr1-16133337-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 293419.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-16133337-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=2.65 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00527 (803/152266) while in subpopulation AMR AF= 0.0083 (127/15302). AF 95% confidence interval is 0.0072. There are 2 homozygotes in gnomad4. There are 382 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 804 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPHA2	NM_004431.5	c.1896G>A	p.Leu632=	synonymous_variant	11/17	ENST00000358432.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPHA2	ENST00000358432.8	c.1896G>A	p.Leu632=	synonymous_variant	11/17	1	NM_004431.5	P1
EPHA2	ENST00000462805.1	n.114G>A		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.00528 AC: 804 AN: 152148 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00186

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00838

Gnomad ASJ AF: 0.00893

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.000564

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00775

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00561 AC: 1410 AN: 251242 Hom.: 6 AF XY: 0.00571 AC XY: 776 AN XY: 135800

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.00645

Gnomad ASJ exome AF: 0.0113

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00167

Gnomad FIN exome AF: 0.00125

Gnomad NFE exome AF: 0.00798

Gnomad OTH exome AF: 0.0101

GnomAD4 exome AF: 0.00766 AC: 11189 AN: 1461602 Hom.: 51 Cov.: 33 AF XY: 0.00751 AC XY: 5458 AN XY: 727114

Gnomad4 AFR exome AF: 0.00158

Gnomad4 AMR exome AF: 0.00725

Gnomad4 ASJ exome AF: 0.0101

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00196

Gnomad4 FIN exome AF: 0.00143

Gnomad4 NFE exome AF: 0.00875

Gnomad4 OTH exome AF: 0.00830

GnomAD4 genome AF: 0.00527 AC: 803 AN: 152266 Hom.: 2 Cov.: 33 AF XY: 0.00513 AC XY: 382 AN XY: 74446

Gnomad4 AFR AF: 0.00185

Gnomad4 AMR AF: 0.00830

Gnomad4 ASJ AF: 0.00893

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00331

Gnomad4 FIN AF: 0.000564

Gnomad4 NFE AF: 0.00775

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00763 Hom.: 6

Bravo AF: 0.00589

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0101

EpiControl AF: 0.00925

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 22, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	EPHA2: BP4, BS2 -

Cataract 6 multiple types Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	- -
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. -

EPHA2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 30, 2023

This variant is classified as 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
BayesDel_noAF	Benign	-0.58
Cadd	Benign	6.4
Dann	Benign	0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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

Other links and lift over

dbSNP: rs55655135; hg19: chr1-16459832;