rs10907223

chr1-16133250-G-Achr1-16133250-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004431.5(EPHA2):c.1983C>T(p.Leu661=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0618 in 1,613,688 control chromosomes in the GnomAD database, including 8,671 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (3722 hom., cov: 33)
  • Exomes 𝑓: 0.053 (4949 hom.)
• Consequence: EPHA2 NM_004431.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.30

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=-0.59).
• BP6: Variant 1-16133250-G-A is Benign according to our data. Variant chr1-16133250-G-A is described in ClinVar as [Benign]. Clinvar id is 259389.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-16133250-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.3 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.402 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPHA2	NM_004431.5	c.1983C>T	p.Leu661=	synonymous_variant	11/17	ENST00000358432.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPHA2	ENST00000358432.8	c.1983C>T	p.Leu661=	synonymous_variant	11/17	1	NM_004431.5	P1
EPHA2	ENST00000462805.1	n.201C>T		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.150 AC: 22806 AN: 151970 Hom.: 3709 Cov.: 33

Gnomad AFR AF: 0.407

Gnomad AMI AF: 0.151

Gnomad AMR AF: 0.0880

Gnomad ASJ AF: 0.0648

Gnomad EAS AF: 0.117

Gnomad SAS AF: 0.0982

Gnomad FIN AF: 0.0579

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0340

Gnomad OTH AF: 0.123

GnomAD3 exomes AF: 0.0842 AC: 21151 AN: 251182 Hom.: 1983 AF XY: 0.0776 AC XY: 10532 AN XY: 135790

Gnomad AFR exome AF: 0.416

Gnomad AMR exome AF: 0.0786

Gnomad ASJ exome AF: 0.0571

Gnomad EAS exome AF: 0.118

Gnomad SAS exome AF: 0.0989

Gnomad FIN exome AF: 0.0511

Gnomad NFE exome AF: 0.0383

Gnomad OTH exome AF: 0.0747

GnomAD4 exome AF: 0.0526 AC: 76826 AN: 1461600 Hom.: 4949 Cov.: 33 AF XY: 0.0527 AC XY: 38299 AN XY: 727134

Gnomad4 AFR exome AF: 0.421

Gnomad4 AMR exome AF: 0.0829

Gnomad4 ASJ exome AF: 0.0584

Gnomad4 EAS exome AF: 0.112

Gnomad4 SAS exome AF: 0.0970

Gnomad4 FIN exome AF: 0.0510

Gnomad4 NFE exome AF: 0.0333

Gnomad4 OTH exome AF: 0.0736

GnomAD4 genome AF: 0.150 AC: 22865 AN: 152088 Hom.: 3722 Cov.: 33 AF XY: 0.150 AC XY: 11184 AN XY: 74352

Gnomad4 AFR AF: 0.407

Gnomad4 AMR AF: 0.0881

Gnomad4 ASJ AF: 0.0648

Gnomad4 EAS AF: 0.117

Gnomad4 SAS AF: 0.0974

Gnomad4 FIN AF: 0.0579

Gnomad4 NFE AF: 0.0340

Gnomad4 OTH AF: 0.123

Alfa AF: 0.0652 Hom.: 1308

Bravo AF: 0.167

Asia WGS AF: 0.163 AC: 566 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

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 26, 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

Apr 12, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
Cadd	Benign	2.6
Dann	Benign	0.82

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

Other links and lift over

dbSNP: rs10907223; hg19: chr1-16459745; COSMIC: COSV64454189; COSMIC: COSV64454189;