chr1-16133250-G-A

Variant names:

• chr1-16133250-G-A
• rs10907223
• NM_004431.5:c.1983C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004431.5(EPHA2):​c.1983C>T​(p.Leu661Leu) 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:5
• Conservation: PhyloP100: 1.30
• Publications: 21 publications found

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 Gene-Disease associations (from GenCC):

• cataract 6 multiple types

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• early-onset non-syndromic cataract

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• early-onset nuclear cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset posterior polar cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset posterior subcapsular cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• total early-onset cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 259389.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
EPHA2	NM_004431.5	c.1983C>T	p.Leu661Leu	synonymous_variant	Exon 11 of 17	ENST00000358432.8	NP_004422.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPHA2	ENST00000358432.8	c.1983C>T	p.Leu661Leu	synonymous_variant	Exon 11 of 17	1	NM_004431.5	ENSP00000351209.5
EPHA2	ENST00000462805.1	n.201C>T		non_coding_transcript_exon_variant	Exon 2 of 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

GnomAD2 exomes AF: 0.0842 AC: 21151 AN: 251182 AF XY: 0.0776

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 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

African (AFR) AF: 0.421 AC: 14099 AN: 33478

American (AMR) AF: 0.0829 AC: 3706 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.0584 AC: 1524 AN: 26116

East Asian (EAS) AF: 0.112 AC: 4437 AN: 39700

South Asian (SAS) AF: 0.0970 AC: 8369 AN: 86258

European-Finnish (FIN) AF: 0.0510 AC: 2714 AN: 53256

Middle Eastern (MID) AF: 0.0841 AC: 485 AN: 5766

European-Non Finnish (NFE) AF: 0.0333 AC: 37047 AN: 1111934

Other (OTH) AF: 0.0736 AC: 4445 AN: 60386

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

African (AFR) AF: 0.407 AC: 16873 AN: 41410

American (AMR) AF: 0.0881 AC: 1348 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0648 AC: 225 AN: 3472

East Asian (EAS) AF: 0.117 AC: 607 AN: 5188

South Asian (SAS) AF: 0.0974 AC: 470 AN: 4824

European-Finnish (FIN) AF: 0.0579 AC: 615 AN: 10624

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0340 AC: 2310 AN: 67952

Other (OTH) AF: 0.123 AC: 260 AN: 2114

Alfa AF: 0.0739 Hom.: 1998

Bravo AF: 0.167

Asia WGS AF: 0.163 AC: 566 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Cataract 6 multiple types Benign:2

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	2.6
DANN	Benign	0.82
PhyloP100		1.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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